Piperidine derivatives useful as neurokinin antagonists

ABSTRACT

Compounds of formula I ##STR1## wherein Q 1 , Q 2 , Q 3 , and Q 4  have any of the meanings given in the specification, their N-oxides, and their pharmaceutically acceptable salts are nonpeptide antagonists of neurokinin A and useful for the treatment of asthma, etc. Also disclosed are pharmaceutical compositions, processes for preparing the compounds of formula I and intermediates.

This invention concerns novel heterocyclic compounds which antagonizethe pharmacological actions of one of the endogenous neuropeptidetachykinins known as neurokinins, particularly at the neurokinin 2 (NK2)receptor. The novel heterocyclic compounds are useful whenever suchantagonism is desired. Thus, such compounds may be of value in thetreatment of those diseases in which an NK2 receptor is implicated, forexample, in the treatment of asthma and related conditions. Theinvention also provides pharmaceutical compositions containing the novelheterocyclic compounds for use in such treatment, methods for their use,and processes and intermediates for the manufacture of the novelheterocyclic compounds.

The mammalian neurokinins comprise a class of peptide neurotransmitterswhich are found in the peripheral and central nervous systems. The threeprincipal neurokinins are Substance P (SP), Neurokinin A (NKA) andNeurokinin B (NKB). There are also N-terminally extended forms of atleast NKA. At least three receptor types are known for the threeprincipal neurokinins. Based upon their relative selectivities favoringthe neurokinin agonists SP, NKA and NKB, respectively, the receptors areclassified as neurokinin 1 (NK1) neurokinin 2 (NK2) and neurokinin 3(NK3) receptors, respectively. In the periphery, SP and NKA arelocalized in C-afferent sensory neurons, which neurons are characterizedby non-myelinated nerve endings known as C-fibers, and are released byselective depolarization of these neurons, or selective stimulation ofthe C-fibers. C-Fibers are located in the airway epithelium, and thetachykinins are known to cause profound effects which clearly parallelmany of the symptoms observed in asthmatics. The effects of release orintroduction of tachykinins in mammalian airways includebronchoconstriction, increased microvascular permeability, vasodilationand activation of mast cells. Thus, the tachykinins are implicated inthe pathophysiology and the airway hyperresponsiveness observed inasthmatics; and blockade of the action of released tachykinins may beuseful in the treatment of asthma and related conditions. Peptidic NK2antagonists have been reported. For example, a cyclic hexapeptide knownas L-659,877 has been reported as a selective NK2 antagonist.Nonpeptidic NK2 antagonists also have been reported, for example inEuropean Patent Application, Publication Number (EPA) 428434, EPA474561, EPA 512901, EPA 512902 and EPA 515240, as well as in EPA 559538,EPA 625509 and EPA 630887 and International Patent ApplicationPublication Number WO 94/148,184. We have discovered a series ofnonpeptidic NK2 antagonists, and this is the basis for our invention.

According to the invention, there is provided a Compound of theinvention which is a compound of formula I (formula set out hereinbelowfollowing the Examples, together with other formulae denoted by Romannumerals) wherein

Q¹ is a radical (attached at Z) selected from the group of radicals offormulae Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ij and Ik wherein

for a radical of formula Ia, Z^(a) is nitrogen or a group CR^(ad) inwhich R^(ad) is hydrogen or R^(ad) together with R^(ac) and the existingcarbon to carbon bond forms a double bond; R^(aa) is Ar or Het; R^(ab)is hydrogen and R^(ac) is hydrogen or hydroxy or R^(ac) together withR^(ad) and the existing carbon to carbon bond forms a double bond, orR^(ac) and R^(ad) together form a diradical --(CH₂)_(j) -- in which j isan integer from 1 to 5; or R^(ab) and R^(ac) together form a diradical--(CH²)_(k) -- in which k is an integer from 2 to 6, or R^(ab) andR^(ac) together are oxo or dialkylaminoalkyloxyimino of formula═N--O--(CH₂)_(q) --NR^(ae) R^(af) in which q is the integer 2 or 3 andR^(ae) and R^(af) are independently hydrogen or (1-4C)alkyl, or theradical NR^(ae) R^(af) is pyrrolidino, piperidino or morpholino;

for a radical of formula Ib, Z^(b) is a substituted imino group R^(ba) Nor R^(ba) CH₂ N in which R^(ba) is (3-7C)cycloakyl, Ar or Het; or Z^(b)is a disubstituted methylene group R^(bb) (CH₂)_(p) --C--R^(bc) in whichR^(bb) is Ar or Het; p is the integer 0 or 1; and R^(bc) is hydrogen,hydroxy, (1-4C)alkoxy, (1-4C)alkanoyloxy, COOR^(bd) (wherein R^(bd) ishydrogen or (1-3C)alkyl), cyano, NR^(be) R^(bf) or SR^(bg) in whichR^(be) and R^(bf) are independently hydrogen, (1-4C)alkyl,(1-4C)hydroxyalkyl or (1-4C)alkanoyl, or the radical NR^(be) R^(bf) ispyrrolidino, piperidino or morpholino; and R^(bg) is hydrogen or(1-4C)alkyl; or R^(bc) forms a double bond with the carbon atom to whichit is bonded and with the adjacent carbon atom in the piperidine ring;

or Z^(b) is a disubstituted methylene group R^(bh) CR^(bi) which forms aspirocyclic ring wherein R^(bh) is phenyl which is joined by anortho-substituent diradical X^(b) to R^(bi) in which the phenyl R^(bh)may bear a further substituent selected from halo, (1-3C)alkyl,(1-3C)alkoxy, hydroxy, (1-3C)alkylthio, (1-3C)alkylsulfinyl and(1-3C)alkylsulfonyl; the diradical X^(b) is methylene, carbonyl orsulfonyl; and R^(bi) is oxy or imino of formula --NR^(bj) -- in whichR^(bj) is hydrogen or (1-3C)alkyl;

for a radical of formula Ic, R^(ca) is Ar or Het; and Z^(c) is oxo,thio, sulfinyl, sulfonyl or imino of formula --NR^(cb) -- in whichR^(cb) is (1-3C)alkyl or R^(cc) R^(cd) N--(CH₂)_(q) -- in which q is theinteger 2 or 3 and in which R^(cc) and R^(cd) are independently hydrogenor (1-3C)alkyl or the radical R^(cc) R^(cd) N is pyrrolidino, piperidinoor morpholino;

for a radical of formula Id, R^(da) is hydrogen, (1-6C)alkyl, Ar, Het,α-hydroxybenzyl, styryl, or R^(db) -(1-3C)alkyl in which R^(db) is aryl,pyridyl, pyridylthio or 1-methyl-2-imidazolylthio in which an aromaticgroup or portion of R^(da) may bear one or more halo, hydroxy,(1-4C)alkyl or (1-4C)alkoxy substituents; X_(d) is oxy or --CHR^(dc) --;R^(dc) is hydrogen, hydroxy, (1-3C)alkoxy, (1-4C)alkanoyloxy, NR^(dd)R^(de) or (1-4C)alkanoylamino; R^(dd) and R^(de) are independentlyhydrogen or (1-4C)alkyl or the radical NR^(dd) R^(de) is pyrrolidino,piperidino or morpholino; p is the integer 0 or 1; and Z^(d) is a singlebond (except when R^(da) is hydrogen or p is 1), methylene or carbonyl;

for a radical of formula Ie, J^(e) is oxygen, sulfur or NR^(ea) in whichR^(ea) is hydrogen or (1-3C)alkyl; R^(eb) is hydrogen, (1-6C)alkyl whichmay bear a hydroxy substituent and/or one to three fluoro substituents,(3-6C)alkenyl (in which a vinyl carbon is not bound to nitrogen),2-hydroxyethyl, (3-7C)cyloalkyl, Ar or Het; R^(ec) is hydrogen,(1-6C)alkyl which may bear a hydroxy substituent and/or one to threefluoro substituents, (3-6C)cycloalkyl, (1-5C)alkoxy (only when J^(e) isoxygen), (3-6C)cycloalkoxy (only when J^(e) is oxygen), or an aminogroup of formula NR^(ed) R^(ee) containing zero to seven carbon atoms inwhich each of R^(ed) and R^(ee) is independently hydrogen, (1-5C)alkylor (3-6C)cycloalkyl, or the radical NR^(ed) R^(ee) is pyrrolidino,piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl(which piperazinyl group may bear a (1-3C)alkyl substituent at the4-position);

for a radical of formula If, J^(f) is oxygen, sulfur or NR^(fa) in whichR^(fa) is hydrogen or (1-3C)alkyl; L^(f) is a divalent hydrocarbon groupin which the 1-position is bound to the carbon bearing the group J^(f),the divalent group L^(f) being selected from trimethylene,cis-propenylene, tetramethylene, cis-butenylene, cis-but-3-enylene,cis,cis-butadienylene, pentamethylene and cis-pentenylene which divalentgroup L^(f) itself may bear one or two methyl substituents;

for a radical of formula Ig, Z^(g) is (1-8C)alkyl or (3-8C)cycloalkylwhich may bear one or more substituents selected from the groupconsisting of halo, (3-6C)cycloalkyl, cyano, nitro, hydroxy,(1-4C)alkoxy, (1-5C)alkanoyloxy, aroyl, heteroaroyl, oxo, imino (whichmay bear a (1-6C)alkyl, (3-6C)cycloalkyl, (1-5C)alkanoyl or aroylsubstituent), hydroxyimino (which hydroxyimino may bear a (1-4C)alkyl ora phenyl substituent on the oxygen), an amino group of formula NR^(ga)R^(gb), an amino group of formula NR^(gc) R^(gd), an amidino group offormula C(═NR^(gg))NR^(ge) R^(gf), and a carbamoyl group of formulaCON(OR^(gh))R^(gi), but excluding any radical wherein a hydroxy and anoxo substituent together form a carboxy group, wherein an amino group offormula NR^(ga) R^(gb) contains zero to seven carbon atoms and each ofR^(ga) and R^(gb) is independently hydrogen, (1-5C)alkyl or(3-6C)cycloalkyl, or the radical NR^(ga) R^(gb) is pyrrolidino,piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl(which piperazinyl may bear a (1-3C)alkyl substituent group at the4-position); and wherein R^(gc) is hydrogen or (1-3C)alkyl and R^(gd) is(1-5C)alkanoyl, aroyl or heteroaroyl; or R^(gd) is a group of formulaC(═Jg)NR^(ge) R^(gf) in which J^(g) is oxygen, sulfur, NR^(gg) orCHR^(gj) ; and wherein the amino group NR^(ge) R^(gf) contains zero toseven carbon atoms and each of R^(ge) and R^(gf) is independentlyhydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, or the radical NR^(ge) R^(gf)is pyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide)or piperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent atthe 4-position) or R^(ge) is hydrogen or (1-4C)alkyl and R^(gf) togetherwith R^(gg) forms an ethylene or trimethylene group; R^(gg) is hydrogen,(1-4C)alkyl or together with R^(gf) forms an ethylene or trimethylenegroup; R^(gj) is cyano, nitro or SO₂ R^(gk) and R^(gk) is (1-4C)alkyl orphenyl; R^(gh) and R^(gi) are independently (1-3C)alkyl; and in which acyclic group which is a substituent on Z^(g) or formed by substitutionon Z^(g) may bear one or more (1-3C)alkyl groups on carbon as furthersubstituents; and in which any aryl or heteroaryl group which is a partof the group Z^(g) may bear one or more halo, (1-4C)alkyl, (1-4C)alkoxy,cyano, trifluoromethyl or nitro substituents;

for a radical of formula Ih, G^(h) denotes a single bond, a double bondor a divalent hydrocarbon radical; J^(h) denotes a radical joined to thering by a single bond if G^(h) denotes a double bond or, otherwise, aradical joined by a double bond; M^(h) denotes a heteroatom asubstituted heteroatom, or a single bond; and L^(h) denotes ahydrocarbon radical in which the 1-position is attached to M^(h) ;wherein the values of G^(h), J^(h), M^(h) and L^(h) are selected from

(a) G^(h) is a single bond; J^(h) is oxo or thioxo; M^(h) is oxy, thioor NR^(ha) ; and L^(h) is L^(ha) ;

(b) G^(h) is a single bond; J^(h) is NR^(hb) ; M^(h) is NR^(ha) ; andL^(h) is L^(ha) ;

(c) G^(h) is a double bond, J^(h) is OR^(ha), SR^(ha) or NR^(hc) R^(hd); M^(h) is nitrogen; and L^(h) is L^(ha) ;

(d) G^(h) is methylene which may bear one or two methyl substituents;J^(h) is oxo, thio or NR^(he) ; M^(h) is oxy, thio, sulfinyl, sulfonylor NR^(ha) ; and L^(h) is L^(hb) ;

(e) G^(h) is a single bond; J^(h) is oxo, thioxo or NR^(he) ; M^(h) isnitrogen; and L^(h) is L^(hc) ;

(f) G^(h) is methine, which may bear a (1-3C)alkyl substituent; J^(h) isoxo, thioxo or NR^(he) ; M^(h) is nitrogen; and L^(h) is L^(hd) ;

(g) G^(h) is cis-vinylene, which may bear one or two methylsubstituents; J^(h) is oxo, thioxo, or NR^(he) ; M^(h) is nitrogen; andL^(h) is L^(he) ; and

(h) G^(h) is a single bond; J^(h) is oxo or thioxo; M^(h) is a singlebond; and L^(h) is L^(hf) ; wherein

R^(ha) is hydrogen or (1-3C)alkyl; R^(hb) is hydrogen, (1-3C)alkyl,cyano, (1-3C)alkylsulfonyl or nitro; R^(hc) and R^(hd) are independentlyhydrogen or (1-3C)alkyl or the radical NR^(hc) R^(hd) is pyrrolidino,piperidino, morpholino, thiomorpholino (or its S-oxide) or piperazinyl(which piperazinyl may bear a (1-3C)alkyl substituent at the4-position); R^(he) is hydrogen or (1-3C)alkyl; L^(ha) is ethylene,cis-vinylene, trimethylene or tetramethylene which radical L^(ha) itselfmay bear one or two methyl substituents; L^(hb) is ethylene ortrimethylene which radical L^(hb) itself may bear one or two methylsubstituents; L^(hc) is prop-2-en-1-yliden-3-yl, which radical L^(hc)itself may bear one or two methyl substituents; L^(hd) is cis-vinylene,which radical L^(hd) itself may bear one or two methyl substituents;L^(he) is methine, which radical L^(he) itself may bear a (1-3C)alkylsubstituent; and L^(hf) is 4-oxabutan-1,4-diyl;

for a radical of formula Ij, X^(j) is (1-6C)alkyl, --CH₂ OR^(ja), --CH₂SR^(ja), --CH₂ S(O)R^(jg), --CH₂ S(O)₂ R^(jg), --COR^(ja), --COOR^(ja),--C(═J^(ja))NR^(jb) R^(jc), --C(R^(ja))(OR^(jd))(OR^(je)), --CH₂N(R^(ja))C(═J^(ja))R^(jf), --CH₂ N(R^(ja))COOR^(jg) or --CH₂N(R^(ja))C(═J^(ja))NR^(jb) R^(jc) ;

B^(j) is a direct bond and L^(j) is a hydrocarbon chain in which the1-position is bound to B^(j) and L^(j) is selected from trimethylene,tetramethylene, cis-1-butenylene and cis,cis-butadienylene; or B^(j) isN(R^(jh)) and L^(j) is a hydrocarbon chain selected from ethylene,trimethylene and cis-vinylene; or B^(j) is N and L^(j) is a hydrocarbonchain in which the 1-position is bound to B^(j) and L^(j) iscis,cis-prop-2-en-1-ylidin-3-yl; J^(j) and J^(ja) are independentlyoxygen or sulfur; R^(ja), R^(jf) and R^(jh) are independently hydrogenor (1-6C)alkyl; R^(jb) and R^(jc) are independently hydrogen or(1-6C)alkyl; or the radical NR^(jb) R^(jc) is pyrrolidino, piperidino,morpholino, thiomorpholino (or its S-oxide) or piperazinyl (whichpiperazinyl may bear a (1-3C)alkyl substituent at the 4-position);R^(jd) and R^(je) are independently (1-3C)alkyl or together form adivalent hydrocarbon chain selected from ethylene and trimethylene;R^(jg) is (1-6C)alkyl; and

for a radical of formula Ik, Z^(k) is a nitrogen linked radical offormula II wherein E¹, E², E³ and E⁴ form a divalent four membered chain(--E¹ ═E² --E³ ═E⁴ --) in which each of E¹, E², E³ and E⁴ is methine; orin which one or two of E¹, E², E³ and E⁴ is nitrogen and the remainingE¹, E², E³ and E⁴ are methine; and further wherein one or more of E¹,E², E³ and E⁴ which is methine may bear a halo, (1-3C)alkyl, hydroxy,(1-3C)alkoxy, (1-3C)alkylthio, (1-3C)alkylsulfinyl or(1-3C)alkylsulfonyl substituent; and wherein the radicals F^(k), G^(k),and I^(k) (X^(k)) are selected from

(a) G^(k) is a direct bond, I^(k) (X^(k)) is a radical having theformula ═C(Z^(k))-- and F^(k) is a radical selected from --CH═ and --N═;

(b) G^(k) is a direct bond, I^(k) (X^(k)) is a radical having theformula --C(═J^(k))-- and F^(k) is a radical selected from--N(R^(kf))--, --CH₂ --CH₂ --, --CH═CH--, --CH₂ --N(R^(kf))-- and--CH═N--;

(c) G^(k) is a radical having the formula --CH₂ --, I^(k) (X^(k)) is aradical having formula --C(═J^(k))-- and F^(k) is selected from --CH₂ --and --N(R^(kf))--; and

(d) G^(k) is selected from --CH₂ --, --CH₂ --CH₂ --, --CH═CH-- and--N═CH--, I^(k) (X^(k)) is a radical having the formula --C(═J^(k))--and F^(k) is a direct bond; wherein

J^(k) is oxygen or sulfur; Z^(k) is --OR^(ka), --SR^(ka), --COR^(ka),--COOR^(ka), --C(═J^(ka))NR^(kb) R^(kc) or--C(R^(ka))(OR^(kd))(OR^(ke)); J^(ka) is oxygen or sulfur; R^(ka) andR^(kf) are independently hydrogen or (1-6C)alkyl; R^(kb) and R^(kc) areindependently hydrogen or (1-6C)alkyl; or the radical NR^(kb) R^(kc) ispyrrolidino, piperidino, morpholino, thiomorpholino (or its S-oxide) orpiperazinyl (which piperazinyl may bear a (1-3C)alkyl substituent at the4-position); R^(kd) and R^(ke) are independently (1-3C)alkyl or R^(kd)and R^(ke) together form ethylene or trimethylene; or Z^(k) is an imidoradical selected from phthalimido, succinimido, maleimido, glutarimidosand 3-oxa-, 3-thia- and 3-azaglutarimido, in which the imido radical maybear one or more (1-3C)alkyl substituents and, in addition, the aromaticportion of the phthalimido may bear one or more halo, hydroxy or(1-3C)alkoxy substituents; and wherein

for a radical Q¹, Ar is a phenyl radical or an ortho-fused bicycliccarbocyclic radical of nine of ten ring atoms in which at least one ringis aromatic, which radical Ar may be unsubstituted or may bear one ormore substituents selected from halo, cyano, trifluoromethyl,(1-4C)alkyl, (1-4C)alkoxy, methylenedioxy, hydroxy, mercapto, --S(O)_(n)R^(xa), (1-5C)alkanoyl, (1-5C)alkanoyloxy, nitro, NR^(xb) R^(xc),NR^(xd) R^(xe), C(═NR^(xf))NR^(xg) R^(xh), CONR^(xb) R^(xc) andCOOR^(xj) wherein n is the integer 0, 1, or 2; R^(xa) is (1-6C)alkyl,(3-6C)cycloalkyl or phenyl (which phenyl may bear a halo,trifluoromethyl, (1-3C)alkyl or (1-3C)alkoxy substitutent); the radicalNR^(xb) R^(xc) contains zero to seven carbons and each of R^(xb) andR^(xc) is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, orthe radical NR^(xb) R^(xc) is pyrrolidino, piperidino, morpholino,thiomorpholine (or its S-oxide) or piperazinyl (which piperazinyl maybear a (1-3C)alkyl substituent at the 4-position); and wherein R^(xd) ishydrogen or (1-4C)alkyl and R^(xe) is (1-5C)alkanoyl, benzoyl; or agroup of formula C(═J^(x))NR^(xg) R^(xh) in which J^(x) is oxygen,sulfur, NR^(xf) or CHR^(xi) ; R^(xf) is hydrogen, (1-5C)alkyl ortogether with R^(xg) forms an ethylene or trimethylene diradical, theradical NR^(xg) R^(xh) contains zero to 7 carbons and each of R^(xg) andR^(xh) is independently hydrogen, (1-5C)alkyl or (3-6C)cycloalkyl, orthe radical NR^(xg) R^(xh) is pyrrolidino, piperidino, morpholino,thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl maybear a (1-3C)alkyl substituent at the 4-position); or R^(xg) togetherwith R^(xf) forms an ethylene or trimethylene diradical and R^(xh) ishydrogen or (1-5C)alkyl; R^(xi) is cyano, nitro, (1-5C)alkylsulfonyl orphenylsulfonyl; and R^(xj) is hydrogen, (1-5C)alkyl or benzyl; and Hetis a radical (or stable N-oxide thereof) attached via a ring carbon of amonocyclic aromatic ring containing five or six ring atoms consisting ofcarbon and one to four heteroatoms selected from oxygen, sulfur andnitrogen, or an ortho-fused bicyclic heterocycle derived therefrom byfusing a propenylene, trimethylene, tetramethylene or benz-diradical,which radical Het may be unsubstituted or may be substituted on carbonby one or more of the substituents defined above for Ar and may besubstituted on nitrogen by (1-3C)alkyl;

Q² is a mono valent radical selected from hydroxy, (1-3C)alkoxy, --SR⁵,--OC(═O)R⁶, --OC(═O)NR⁷ R⁸ ; or divalent radical selected from thioxoand oxo;

R⁵ is hydrogen, (1-3C)alkanoyl, (1-3C)alkyl, phenyl, orphenyl(1-3C)alkyl, wherein any phenyl may optionally be substituted by1-3 substituents selected from halo, (1-3C)alkyl, and (1-3C)alkoxy;

R⁶ is (1-4C)alkyl, phenyl, or phenyl(1-3C)alkyl, wherein any phenyl mayoptionally be substituted by 1-3 substituents selected from halo,(1-3C)alkyl, and (1-3C)alkoxy;

R⁷ and R⁸ are independently hydrogen, (1-4C)alkyl, phenyl, orphenyl(1-3C)alkyl, wherein any phenyl may optionally be substituted by1-3 substituents selected from halo, (1-3C)alkyl, and (1-3C)alkoxy;

Q³ is hydrogen or (1-3C)alkyl;

Q⁴ is phenyl which may bear one or two substituents independentlyselected from halo, trifluoromethyl, hydroxy, (1-3C)alkoxy, (1-3C)alkyland methylenedioxy; or Q⁴ is thienyl, imidazolyl, benzo[b]thiophenyl ornaphthyl any of which may bear a halo substituent; or Q⁴ is biphenylyl;or Q⁴ is carbon-linked indolyl which may bear a benzyl substituent atthe 1-position;

T is a carbon-linked five-membered aromatic ring containing 2-3nitrogens, which is substituted at a ring position adjacent to thecarbon-link by a group Q⁵ ; and

Q⁵ is (1-6C)alkyl (which may contain a double or triple bond),(3-6C)cycloalkyl (which may contain a double bond), (3-6C)oxacycloalkyl(which may contain a double bond), aryl, aryl(1-3C)alkyl, or 5- or6-membered heteroaryl (or N-oxide thereof) consisting of carbon and oneto four heteroatoms selected from oxygen, sulfur and nitrogen, in whichan aryl or heteroaryl radical or portion of a radical may bear one ormore substituents on carbon selected from (1-3C)alkyl, (1-3C)alkoxy,methylenedioxy, halogeno, hydroxy, (1-4C)acyloxy and NR^(A) R^(B) inwhich R^(A) and R^(B) are independently hydrogen or (1-3C)alkyl, orR^(A) is hydrogen or (1-3C)alkyl and R^(B) is (1-4C)acyl;

or the N-oxide of a piperidino nitrogen indicated by Δ (or of eitherbasic piperazinyl nitrogen of Q¹ when Z^(a) is nitrogen);

or a pharmaceutically acceptable salt thereof;

or a quaternary ammonium salt thereof in which the piperidino nitrogenindicated by Δ (or either basic piperazinyl nitrogen of Q¹ when Z^(a) isnitrogen) is a quadricovalent ammonium nitrogen wherein the fourthradical on the nitrogen R¹ is (1-4C)alkyl or benzyl and the associatedcounterion A is a pharmaceutically acceptable anion.

A subgroup of the invention is a compound of formula I wherein Q² is amono valent or divalent radical selected from hydroxy, acetoxy,(1-3C)alkoxy and oxo, wherein Q¹, Q², T and Q⁵ have any of the meaningsgiven above for a compound of formula I;

or the N-oxide of a piperidino nitrogen indicated by Δ (or of eitherbasic piperazinyl nitrogen of Q¹ when Z^(a) is nitrogen);

or a pharmaceutically acceptable salt thereof;

or a quaternary ammonium salt thereof in which the piperidino nitrogenindicated by Δ (or either basic piperazinyl nitrogen of Q¹ when Z^(a) isnitrogen) is a quadricovalent ammonium nitrogen wherein the fourthradical on the nitrogen R¹ is (1-4C)alkyl or benzyl and the associatedcounterion A is a pharmaceutically acceptable anion.

Another subgroup of the invention is a compound of formula III, or apharmaceutically acceptable salt thereof, wherein Q^(1a) is a radical offormula Q¹ defined above for a compound of formula I in which Z denotesa nitrogen and Q², T and Q⁵ have any of the meanings given above for acompound of formula I.

It will be appreciated that a compound of formula I (or III) containsone or more asymmetrically substituted carbon atoms such that such acompound may be isolated in optically active, racemic and/ordiastereomeric forms. A compound may exhibit tautomerization. A compoundmay exhibit polymorphism. It is to be understood that the presentinvention encompasses any racemic, optically-active, diastereomeric,tautomeric, polymorphic or stereoisomeric form, or mixture thereof,which form possesses NK2 antagonist properties, it being well known inthe art how to prepare optically-active forms (for example, byresolution of the racemic form or by synthesis from optically-activestarting materials) and how to determine the NK2 antagonist propertiesby the standard tests described hereinafter. It may be preferred to usethe compound of formula I (or III) in an optically pure form which ischaracterized as containing, for example, at least 95%, 98% or 99%enantiomeric excess of a particular form. For example, it may bepreferred to use the compound of formula I (or III), or a particulardiastereomer thereof, in a form which is characterized as containing atleast 95%, 98% or 99% enantiomeric excess of the form with the (R)- orthe (S)-configuration at the center(s) indicated by * in the formulae.

In this specification R^(aa), R^(ab), R¹, R², et cetera stand forgeneric radicals and have no other significance. It is to be understoodthat the generic term "(1-6C)alkyl" includes both straight and branchedchain alkyl radicals but references to individual alkyl radicals such as"propyl" embrace only the straight chain ("normal") radical, branchedchain isomers such as "isopropyl" being referred to specifically. Asimilar convention applies to other generic groups, for example, alkoxy,alkanoyl, et cetera. Halo is fluoro, chloro, bromo or iodo. Aryl (exceptwhere more specifically defined) denotes a phenyl radical or anortho-fused bicyclic carbocyclic radical having abut nine to ten ringatoms in which at least one ring is aromatic. Heteroaryl (except wheremore specifically defined) encompasses a radical attached via a ringcarbon of a monocyclic aromatic ring containing five ring atomsconsisting of carbon and one to four heteroatoms selected from oxygen,sulfur and nitrogen or containing six ring atoms consisting of carbonand one or two nitrogens, as well as a radical of an ortho-fusedbicyclic heterocycle of about eight to ten atoms derived therefrom,particularly a benz-derivative or one derived by fusing a propenylene,trimethylene of tetramethylene diradical thereto, as well as a stableN-oxide thereof. Aroyl is arylcarbonyl; heteroaroyl isheteroarylcarbonyl.

A pharmaceutically acceptable salt is one made with an acid whichprovides a physiologically acceptable anion.

Particular values are listed below for radicals or portions thereof (forexample, particular values for (1-3C)alkyl provide particular values forthe alkyl portion of (1-3C)alkoxy or (1-3C)alkylsulfinyl), substituentsand ranges for a compound of formula I or formula III as described abovefor illustration only and they do not exclude other defined values orother values within defined ranges for the radicals and substituents.

A particular value for Ar is phenyl which may be unsubstituted or maybear a chloro, methyl, methoxy, hydroxy or methylsulfinyl substituent. Aparticular value for Het is furyl, thienyl, 2-imidazolyl,1,3,4-oxadiazol-2-yl, pyridyl or pyrimidinyl which ring may beunsubstituted or may bear a chloro, methyl, methoxy, hydroxy,methylsulfinyl, methoxycarbonyl or ethoxycarbonyl substituent. Aparticular value for aryl is phenyl. A particular value for heteroarylis furyl, pyridyl or pyrimidinyl. A particular value for halo is chloroor bromo. A particular value for (1-3C)alkyl is methyl, ethyl, propyl orisopropyl; for (1-4C)alkyl is methyl, ethyl, propyl, isopropyl, butyl,isobutyl or t-butyl; for (1-5C)alkyl is methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl; for(1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, isopentyl, hexyl or isohexyl; and for (1-8C)alkyl ismethyl, ethyl, propyl, isopropyl, isopentyl, 1-ethylpropyl, hexyl,isohexyl, 1-propylbutyl, or octyl. A particular value for(3-6C)cylcoalkyl is cyclopropyl, cyclopentyl or cyclohexyl; for(3-7C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl;and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl. A particular value for (3-6C)alkenyl isallyl, 2-butenyl or 3-methyl-2-butenyl. A particular value for(1-4C)alkanoyl is formyl, acetyl, propionyl, butyryl or isobutyryl; andfor (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl or pivaloyl.

A more particular value for Ar is phenyl which may be unsubstituted ormay bear a methoxy, hydroxy or methylsulfinyl substituent. A moreparticular value for Het is pyridyl or pyrimidinyl which ring may beunsubstituted or may bear a methoxy, hydroxy or methylsulfinylsubstituent. A more particular value for heteroaryl is pyridyl. A moreparticular value for halo is chloro. A more particular value for(1-3C)alkyl is methyl; for (1-4C)alkyl is methyl or ethyl; for(1-5C)alkyl is methyl, ethyl, propyl or isopropyl; for (1-6C)alkyl ismethyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl; and for(1-8C)alkyl is methyl, ethyl, propyl, isopropyl, 1-ethylpropyl or1-propylbutyl. A more particular value for (3-6C)cylcoalkyl iscyclopropyl or cyclopentyl; for (3-7C)cycloalkyl is cyclopropyl orcyclopentyl; and for (3-8C)cycloalkyl is cyclopropyl, cyclopentyl,cyclohexyl or cycloheptyl. A more particular value for (3-6C)alkenyl isallyl. A more particular value for (1-4C)alkanoyl is formyl or acetyl;and for (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl orisobutyryl.

A particular value for Q¹ is 4-benzylpiperidino,4-(3-methoxyphenyl)piperidino, 4-(2-methylsulfinyl)phenylpiperidino,4-(2-pyridyl)piperidino, 4-(3-pyridyl)piperidino,4-(2-methylsulfinylpyrid-3-ylpiperidino, 4-hydroxy-4-phenylpiperidino,4-acetamido-4-phenylpiperidino, 4-(N-phenylacetamido)piperidino,4-(2-hydroxyethyl)piperidino, 4-(1-hydroxy-1-propylbutyl)piperidino,4-(2-oxopyrrolidin-1-yl)piperidino, 4-(2-oxopiperidino)piperidino,4-(2-thioxopiperidino)piperidino,4-(2-oxoperhydropyrimidin-1-yl)piperidino,4-ethoxycarbonyl-4-(2-oxopiperidino)piperidino,4-methoxycarbonyl-4-(2-oxoperhydropyrimidin-1-yl)piperidino,4-(1-oxoisoindolin-2-yl)piperidino,4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)piperidino,4-(2-oxo-1,2,3,4-tetrahydroquinazolin-3-yl)-iperidino or4-methylaminocarbonyl-4-(2-oxoperhydropyrimidin-1-yl)-piperidino.

A particular value for Q² is hydroxy.

A particular value for Q³ is hydrogen.

A particular value for Q⁴ is 3,4-dichlorophenyl or3,4-methylenedioxyphenyl.

A particular value for T is imidazol-2-yl, pyrazol-4-yl, pyrazol-3-yl,pyrazol-5-yl, triazol-4-yl, or triazol-5-yl.

A particular value for Q⁵ is phenyl.

A particular value for R¹ is methyl or benzyl and for A is, for example,chloride, bromide or methanesulfonate.

A more particular value for Q¹ is 4-hydroxy-4-phenylpiperidino,4-acetamido-4-phenylpiperidino,4-acetamido-4-(2-oxopiperidino)piperidino,4-(1-ethyl-1-hydroxypropyl)piperidino, 4-(2-oxopiperidino)piperidino, or4-(2-oxoperhydropyrimidin-1-yl)piperidino.

A more particular value for T is triazol-5-yl.

A particular group of compounds of formula III is one in which Q^(1a) isa radical of formula If, Ih or Ig and wherein J is oxygen and in whichthe radicals and substituents may have any of the values, particularvalues or more particular values defined above; or a pharmaceuticallyacceptable salt thereof.

A particular group of compounds of formula I is one in which J^(e),J^(f), J^(g), J^(j), J^(ja), J^(k) and J^(ka) are oxygen and J^(h) isoxo; Q² is hydroxy; Q³ is hydrogen; Q⁴ is phenyl which may bear one ortwo substituents selected from halo, trifluoromethyl and methylenedioxy;and Q⁵ is phenyl.

A more particular group of compounds of formula I is one in which Q¹ isa radical of of formula If, Ih or, Ij and wherein J is oxygen and inwhich the radicals and substituents may have any of the values,particular values or more particular values defined above; or apharmaceutically acceptable salt thereof..

It is preferred that the center indicated by * in formula I and formulaIII be of the (S)-configuration and, when Q² is a mono valent radical,that the absolute configuration at the carbon to which Q² is attached be(R). In general, for a compound of formula I or formula III, it ispreferred that the stereochemistry correspond to that identified above,although the designation of an asymmetric center as (R)- or (S)- mayvary with the particular molecule owing to the sequence rules fornomenclature.

Specific compounds of formula I (and of formula III) are described inthe accompanying Examples.

Pharmaceutically acceptable salts of a compound of formula I (or offormula III) include those made with a strong inorganic or organic acidwhich affords a physiologically acceptable anion, such as, for example,hydrochloric, sulfuric, phosphoric, methanesulfonic, orpara-toluenesulfonic acid.

A compound of formula I (or of formula III) may be made by processeswhich include processes known in the chemical art for the production ofstructurally analogous heterocyclic compounds. Such processes andintermediates for the manufacture of a compound of formula I (or offormula III) as defined above are provided as further features of theinvention and are illustrated by the following procedures in which themeanings of generic radicals are as defined above unless otherwiseindicated:

(a) For a compound of formula I in which Z denotes a nitrogen (or for acompound of formula III), alkylating a piperidine of formula IIIa(wherein Q^(1a) is a radical of formula Q¹ defined above for a compoundof formula I in which Z denotes a nitrogen) with an aldehyde of formulaIV (or of formula IVa), by reductive alkylation. The alkylation ispreferably carried out by a conventional reductive alkylation, forexample as described in Example 1, by the in situ, acid-catalyzedformation of an imminum salt, followed by reduction with sodiumcyanoborohydride in alcoholic solvent.

(b) Alkylating a piperidine of formula IIIa with an alkylating agent offormula V (or of formula Va) in which Y is a leaving group. Typicalvalues for Y include for example, iodide, bromide, methanesulfonate,p-toluenesulfonate, trifluoromethanesulfonate, and the like. Thereaction may be carried out under standard conditions, for example in asuitable solvent at a temperature in the range of -20° to 100° C.,preferably in the range of 0° to 50° C.

(c) For an N-oxide of the piperidino nitrogen indicated by Δ of acompound of formula I (or of formula III), oxidizing the piperidinonitrogen indicated by Δ of a compound of formula I using a conventionalprocedure, such as, for example, using hydrogen peroxide in methanol,peracetic acid, 3-chloroperoxybenzoic acid in an inert solvent (such asdichloromethane) or dioxirane in acetone.

(d) For a quaternary ammonium salt of the piperidino nitrogen indicatedby Δ of a compound of formula I (or of formula III), alkylating thepiperidino nitrogen indicated by Δ of the compound of formula I (or offormula III) with an alkylating agent of formula R¹ Y or alkylating apiperidine of formula IIIb with an alkylating agent of formula V,wherein Y is a leaving group, followed, if required, by exchanging thecounterion Y for a different counterion A by a conventional method.Typical values for Y include those listed above. Exchange of counterionsmay conveniently be carried out using a basic ion exchange resin in the"A" form.

(e) For a compound of formula I in which Q¹ is of formula Id, reducingthe double bond of a corresponding starting material of formula VI usinga conventional method.

(f) For a compound of formula I in which Q¹ is of formula Id,substituting the nitrogen of a compound of formula VIa with a radical offormula R^(da) --(X^(d))_(p) --Z^(d) -- using a conventional method.

(g) For a compound of formula I (or of formula III) which bears asulfinyl group, oxidizing the sulfur of a corresponding compound offormula I (or of formula III) which bears a sulfide group using aconventional method.

(h) For a compound of formula I (or of formula III) which bears asulfonyl group, oxidizing a sulfide or sulfinyl group of a correspondingcompound of formula I (or of formula III) using a conventional method.

(i) For a compound of formula I (or of formula III) which bears anaromatic hydroxy group, cleaving the ether of a corresponding compoundof formula I (or of formula III) which bears an aromatic alkoxy groupusing a conventional method.

(j) For a compound of formula I in which Q² is oxo, reacting an amide offormula VII, wherein R2 and R3 are independently (1-3C)alkyl, with asuitable carbanion, for example as described in Example 1.

(k) For a compound of formula I wherein Q² is hydroxy, reducing acorresponding compound of formula I wherein Q² is oxo with a suitablereducing agent, such as for example sodium borohydride as described inExample 2. This method may be preferred for the preparation of compoundsof formula I wherein Q² is hydroxy and Q³ is hydrogen and wherein Q² andQ⁴ are in a syn-configuration, since the syn product may be favored inthis reduction.

(l) Reacting an alkyne of formula VIII with a suitable dipolar reagent,for example diazomethane or azide, to form the heteroaromatic group T,using conventional methods. For example, suitable conditions aredescribed in Examples 3 and 4.

(m) For a compound of formula I wherein Q² is hydroxy, hydrolyzing acorresponding acetoxy compound of formula I using conventional methods.For example, hydrolysis may be carried out under basic aqueousconditions as described in Example 10.

(n) For a compound of formula I wherein Q² is acetoxy or (1-3C)alkoxy,treating a corresponding compound of formula I wherein Q² is hydroxyunder conventional conditions, to form the acetoxy or (1-3C)alkoxygroup.

It may be desired to optionally use a protecting group during all orportions of the above described processes; the protecting group then maybe removed when the final compound is to be formed.

Whereafter, for any of the above procedures, when a pharmaceuticallyacceptable salt of a compound of formula I is required, it may beobtained by reacting the compound of formula I with an acid affording aphysiologically acceptable counterion or by any other conventionalprocedure.

It will also be appreciated that certain of the various optionalsubstituents in the compounds of the invention may be introduced bystandard aromatic substitution reactions or generated by conventionalfunctional group modifications either prior to or immediately followingthe processes above, and as such are included in the process aspect ofthe invention. Such reactions and modifications include, for example,introduction of nitro or halogeno and reduction of nitro. The reagentsand reaction conditions for such procedures are well known in thechemical art.

If not commercially available, the necessary starting materials for theabove procedures may be made by procedures which are selected fromstandard techniques of heterocyclic chemistry, techniques which areanalogous to the synthesis of known, structurally similar compounds(particularly those described in the above noted EPA publications andtheir counterparts), and techniques which are analogous to the abovedescribed procedures or the procedures described in the Examples. Thestarting materials and the procedures for their preparation areadditional aspects of the invention.

General synthetic routes for the preparation of starting materials areoutlined in Schemes I-IV. As outlined in Scheme I, an intermediate offormula IV, wherein Q² is acetoxy, can be prepared from an ester offormula IX, wherein R4 is for example (1-3C)alkyl, by treatment with asuitable base followed by allyl bromide to give the ester X. Hydrolysisof the ester X to the acid XI followed by amide formation gives an amideof formula XII. Treatment of an amide of formula XII with a lanthanum orcerium salt of an anion of a compound of formula XVIII, yields a ketoneXIII. The ketone XIII may be reduced to the alcohol XIV which may beconverted to the acetoxy compound XV. The starting material aldehyde IV,wherein Q² is acetoxy, may be prepared from XV by oxidative cleavage ofthe olefin using conventional procedures, for example as described insub-part f. of Example 7. This synthetic route may be preferred for thepreparation of compounds of formula IV wherein Q² is acetoxy, Q³ ishydrogen, and wherein Q² and Q⁴ are in a syn-configuration, since thesyn product may be favored in the reduction of the ketone XIII to thealcohol XIV.

As outlined in Scheme II, an intermediate of formula IV, wherein Q² isacetoxy, can be prepared from an ester of formula XIX, wherein R4 is forexample (1-3C)alkyl, by reduction to the alcohol XX and conversion tothe aldehyde XXI. Treatment of an aldehyde of formula XXI with alanthanum or cerium salt of an anion of a compound of formula XVIII,yields an alcohol of formula XXII. The starting material aldehyde IV,wherein Q² is acetoxy, may be prepared from XXII by conversion to theacetoxy compound XV followed by oxidative cleavage of the olefin usingconventional proceedures, for example as described in sub-part f. ofExample 7. This synthetic route may be preferred for the preparation ofcompounds of formula IV wherein Q² is acetoxy, Q³ is hydrogen, andwherein Q² and Q⁴ are in an anti-configuration, since the anti productmay be favored in the conversion of the aldehyde XXI to the alcoholXXII.

As outlined in Scheme III, an intermediate of formula VII, wherein Z isnitrogen, may be prepared from an amide of formula XII. Conversion ofXII to an aldehyde of formula XVI, followed by reductive coupling with acompound of formula IIIa yields a starting material of formula VII,wherein Z is nitrogen.

As outlined in Scheme IV, a starting material of formula VIII, whereinQ² is oxo, may be prepared by reaction of an amide of formula VII withan anion of formula XVII, wherein M represents a suitable counterion.For example, suitable conditions for the preparation of an intermediateof formula VIII are described in sub-part a. of Example 3.

Starting material piperidines of formula IIIa may be prepared fromcommercially available materials, for example a 1-protected 4-piperidoneor a 1-protected 4-aminopiperidine, using conventional methods.Compounds of formula IIIa may also be prepared using methods similar tothose described in the Examples hereinbelow. When a compound of formulaIIIa containing a thiocarbonyl group is required, it conveniently may beobtained from a corresponding 1-protected piperidine intermediatecontaining a carbonyl group oxygen by treatment with phosphorouspentasulfide or with Lawesson's reagent,2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,followed by deprotection of the piperidino nitrogen.

A starting material piperidine of formula IIIb may be obtained from apiperidine of formula IIIa by reductive alkylation to introduce thesubstutient R¹, or the compound may be prepared in a manner analogous tothe preparation of a piperidine of formula IIIa.

A starting material of formula VI may be prepared from a correspondingketone of formula VIb by a conventional method, for example bycondensation with a a compound of formula VIc in which R^(dx) and R^(dy)together form a triphenylphosphoranylidene radical or with the anionobtained by deprotonation of a compound of formula VIc wherein R^(dx) isa dimethylphosphono radical and R^(dy) is hydrogen. A compound offormula VIc may be obtained from a compound of formula V using aconventional method. A starting material of formula VIa may be preparedanalogously from a 1-protected 4-pyridone, followed by reduction anddeprotection.

As will be clear to one skilled in the art, a variety of sequences isavailable for preparation of the starting materials, and the sequencesleading to the starting materials and products of the invention may bealtered if appropriate considerations regarding the synthetic methodsand radicals present are followed.

The utility of a compound of the invention or a pharmaceuticallyacceptable salt thereof (hereinafter, collectively referred to as a"Compound") may be demonstrated by standard tests and clinical studies,including those disclosed in the EPA publications noted above, such asEPA 428434 or EPA 474561 (or U.S. Pat. No. 5,236,921), and thosedescribed below.

Neurokinin A (NKA) Receptor-binding Assay (Test A)

The ability of a Compound of the invention to antagonize the binding ofNKA at the NK2 receptor may be demonstrated using an assay using thehuman NK2 receptor expressed in Mouse Erythroleukemia (MEL) cells, asdescribed in: Aharony, D., Little, J., Thomas, C., Powell, S., Berry, D.and Graham, A. Isolation and Pharmacological Characterization of aHampster Neurokinin A Receptor cDNA, Molecular Pharmacology, 1994, 45,9-19. In an initial use of this assay, the IC₅₀ measured for thestandard compound L-659,877 was found to be 30 nM versus ³ H-NKA bindingto MEL.

The selectivity of a Compound for binding at the NK2 receptor may beshown by determining its binding at other receptors using standardassays, for example, one using a tritiated derivative of SP in a tissuepreparation selective for NK1 receptors or one using a tritiatedderivative of NKB in a tissue preparation selective for NK3 receptors.

Guinea Pig Assay (Test B)

The ability of a Compound of the invention to antagonize the action ofan agonist, either NKA or [β-ala⁸ ]-NKA(4-10), in a pulmonary tissue maybe demonstrated using a functional assay in guinea pig trachea, which iscarried out as follows. The chosen agonist is refered to as AGthroughout the description.

Male guinea pigs are killed by a sharp blow to the back of the head. Thetrachea are removed, trimmed of excess tissue and divided into twosegments. Each segment is suspended as a ring between stainless steelstirrups in water-jacketed (37.5° C.) tissue baths containing aphysiological salt solution of the following composition (mM): NaCl,119; KCl 4.6; CaCl₂, 1.8; MgCl₂, 0.5; NaH₂ PO₄, 1; NaHCO₃, 25; glucose,11; thiorphan, 0.001; and indomethacin, 0.005; gassed continuously with95% O₂ -%5 CO₂. Initial tension placed on each tissue is 1 g, which ismaintained throughout a 0.5 to 1.5 hour equilibration period beforeaddition of other drugs. Contractile responses are measured on a Grasspolygraph via Grass FT-03 force transducers.

Tissues are challenged repetitively with a single concentration of AG(10 nM) with intervening 30 min periods with washing to allow thetension to return to baseline levels. The magnitude of the contractionsto AG reaches a constant level after two challenges, and each Compoundis tested for inhibition of responses to AG by addition to the tissuebath 15 minute before the third or subsequent exposure to the agonist.The contractile response to AG in the presence of Compound is comparedto that obtained with the second AG challenge (in the absence ofCompound). Percent inhibition is determined when a Compound produces astatistically significant (p<0.05) reduction of the contraction and iscalculated using the second contractile response as 100%.

Potencies of selected Compounds are evaluated by calculating apparentdissociation constants (K_(B)) for each concentration tested using thestandard equation:

    K.sub.B =[antagonist]/(dose ratio-1)

where dose ratio=antilog[(AG -log molar EC₅₀ without Compound)--(AG -logmolar EC₅₀ with Compound)]. The K_(B) values may be converted to thenegative logarithms and expressed as -log molar K_(B) (i.e. pK_(B)). Forthis evaluation, complete concentration-response curves for AG areobtained in the absence and presence of Compound (30 min incubationperiod) using paired tracheal rings. The potency of AG is determined at50% of its own maximum response level in each curve. The EC₅₀ values areconverted to the negative logarithms and expressed as -log molar EC₅₀.Maximum contractile responses to AG are determined by expressing themaximum response to AG as a percentage of the contraction caused bycarbachol (30 μM), added after the initial equilibration period. When astatistically significant (p<0.05) reduction of the maximum response toAG is produced by a compound, the percent inhibition is calculatedrelative to the percentage of carbachol contraction in the untreated,paired tissue used as 100%.

Guinea Pig Labored Abdominal Breathing (Dyspnea) Assay (Test C)

Activity of a Compound of the invention as an antagonist of NKA at theNK2 receptor also may be demonstrated in vivo in laboratory animals, forexample by adapting a routine guinea pig aerosol test described forevaluation of leukotriene antagonists by Snyder, et al. (Snyder, D. W.,Liberati, N. J. and McCarthy, M. M., Conscious guinea-pig aerosol modelfor evaluation of peptide leukotriene antagonists. J. Pharmacol. Meth.(1988) 19, 219). Using the clear plastic chamber described previously bySnyder et al. to secure guinea pigs for a head-only aerosol exposure tobronchoconstrictor agonists, agonist is administered by aerosol to sixconscious guinea pigs simultaneously during each maneuver. Thetachykinin NK2-selective agonist, [β-ala⁸ ]-NKA(4-10), 3×10⁻⁵ M, isaerosolized from a Devilbiss Model 25 ultrasonic nebulizer into an airstream entering the chamber at a rate of 2 L/minute.

Guinea pigs (275-400 g) are fasted for approximately 16 hours prior toexperimentation. Compounds to be evaluated for blockade of effects of[β-ala⁸ ]-NKA(4-10) or their vehicle (10% PEG400 in saline) areadministered p.o. or i.v. at various times before aerosol agonistchallenge. All animals are pretreated with atropine (10 mg/kg, i.p., 45minutes pretreatment) indomethacin (10 mg/kg, i.p., 30 minutespretreatment), propranolol (5 mg/kg, i.p., 30 minutes pretreatment), andthiorphan (1 mg/ml aerosol for 5 minutes, 15 minutes pretreatment).

Aerosol challenge with the agonist produces an initial increase inrespiratory rate followed by a decrease with early signs of minorinvolvement of the abdominal muscles. The respiratory rate decreasesfurther and the breathing becomes more labored with greater involvementof the abdominal muscles as exposure continues. The distinctlyrecognizable end point is the point where the breathing pattern of theguinea pig is consistently slow, deep, and deliberate, showing markedinvolvement of the abdominal muscles. Time, in seconds, from the onsetof aerosol challenge to this end point is determined for each animal byusing a stopwatch. The animals generally collapse after reaching the endpoint and do not recover from the agonist-induced respiratory distress.Antagonists result in an increase in the time to reach the end point.Animals receive the aerosol administration of agonist for a maximum timeof 780 seconds.

Differences between drug treated groups and corresponding vehicletreated control groups are compared using Student's t-test for unpairedobservations.

Clinical studies to demonstrate the efficacy of a Compound of theinvention may be carried out using standard methods. For example, theability of a Compound to prevent or treat the symptoms of asthma orasthma-like conditions may be demonstrated using a challenge of inhaledcold air or allergen and evaluation by standard pulmonary measurementssuch as, for example, FEV₁ (forced expiratory volume in one second) andFVC (forced vital capacity), analyzed by standard methods of statisticalanalysis.

It will be appreciated that the implications of a Compound's activity inTest A or Test B is not limited to asthma, but rather, that the testprovides evidence of general antagonism of NKA. In general, theCompounds of the invention which were tested demonstrated statisticallysignificant activity in Test A with a K_(i) of 1 μM or much less. Forexample, the compound described in Example 2 was typically found to havea K_(i) of 34 nM. In Test B, a pK_(B) of 5 or greater was typicallymeasured for a Compound of the invention. For example, a pK_(B) of 6.6was measured for the compound described in Example 3. It should be notedthat there may not always be a direct correlation between the activitiesof Compounds measured as K_(i) values in Test A and the values measuredin other assays, such as the pK_(B) measured in Test B.

As discussed above, a compound of formula I or a pharmaceuticallyacceptable salt thereof possesses NKA antagonist properties.Accordingly, it antagonizes at least one of the actions of NKA which areknown to include bronchoconstriction, increased microvascularpermeability, vasodilation and activation of mast cells. Accordingly,one feature of the invention is the use of a compound of formula I or apharmaceutically acceptable salt thereof in the treatment of a diseasein a human or other mammal in need thereof in which NKA is implicatedand antagonism of its action is desired, such as for example thetreatment of asthma or a related disorder. In addition, another featureof the invention is provided by the use of a compound of formula I or asalt thereof as a pharmacological standard for the development andstandardization of new disease models or assays for use in developingnew therapeutic agents for treating the diseases in which NKA isimplicated or for assays for their diagnosis.

When used in the treatment of such a disease, a compound of theinvention is generally administered as an appropriate pharmaceuticalcomposition which comprises a compound of formula I or apharmaceutically acceptable salt thereof as defined hereinbefore and apharmaceutically acceptable diluent or carrier, the composition beingadapted for the particular route of administration chosen. Such acomposition is provided as a further feature of the invention. It may beobtained employing conventional procedures and excipients and binders,and it may be one of a variety of dosage forms. Such forms include, forexample, tablets, capsules, solutions or suspensions for oraladministration; suppositories for rectal administration; sterilesolutions or suspensions for administration by intravenous orintramuscular infusion or injection; aerosols or nebulizer solutions orsuspensions for administration by inhalation; or powders together withpharmaceutically acceptable solid diluents such as lactose foradministration by insufflation.

For oral administration a tablet or capsule containing up to 250 mg (andtypically 5 to 100 mg) of a compound of formula I may conveniently beused. For administration by inhalation, a compound of formula I will beadministered to humans in a daily dose range of, for example, 5 to 100mg, in a single dose or divided into two to four daily doses. Similarly,for intravenous or intramuscular injection or infusion a sterilesolution or suspension containing up to 10% w/w (and typically 0.05 to5% w/w) of a compound of formula I may conveniently be used.

The dose of a compound of formula I to be administered will necessarilybe varied according to principles well known in the art taking accountof the route of administration and the severity of the condition and thesize and age of the patient under treatment. However, in general, thecompound of formula I will be administered to a warm-blooded animal(such as man) so that a dose in the range of, for example, 0.01 to 25mg/kg (and usually 0.1 to 5 mg/kg) is received. It will be understoodthat generally equivalent amounts of a pharmaceutically acceptable saltof a compound of formula I may be used.

The invention will now be illustrated by the following non-limitingexamples in which, unless stated otherwise:

(i) temperatures are given in degrees Celsius (° C.); operations werecarried out at room or ambient temperature, that is, at a temperature inthe range of 18°-25° C.;

(ii) organic solutions were dried over anhydrous magnesium sulfate;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (600-4000 pascals; 4.5-30 mm Hg) with a bathtemperature of up to 60° C.;

(iii) chromatography means flash chromatography on silica gel; reversedphase chromatography means chromatography over octadecylsilane (ODS)coated support having a particle diameter of 32-74μ, known as"PREP-40-ODS" (Art 731740-100 from Bodman Chemicals, Aston, Pa., USA);thin layer chromatography (TLC) was carried out on silica gel plates;radial chromatography refers to chromatography on circular thin layersilica gel plates (Analtech) on a Harrison Research Model 8924Chromatotron.

(iv) in general, the course of reactions was followed by TLC andreaction times are given for illustration only;

(v) melting points are uncorrected and (dec) indicates decomposition;the melting points given are those obtained for the materials preparedas described; polymorphism may result in isolation of materials withdifferent melting points in some preparations;

(vi) final products had satisfactory proton nuclear magnetic resonance(NMR) spectra;

(vii) yields are given for illustration only and are not necessarilythose which may be obtained by diligent process development;preparations were repeated if more material was required;

(viii) when given, NMR data is in the form of delta values for majordiagnostic protons, given in parts per million (ppm) relative totetramethylsilane (TMS) as an internal standard, determined at 300 MHzusing perdeuterio dimethyl sulfoxide (DMSO-d₆) as solvent; conventionalabbreviations for signal shape are used; for AB spectra the directlyobserved shifts are reported; coupling constants (J) are given in Hz; Ardesignates an aromatic proton when such an assignment is made;

(ix) chemical symbols have their usual meanings; SI units and symbolsare used;

(x) reduced pressures are given as absolute pressures in pascals (Pa);elevated pressures are given as gauge pressures in bars;

(xi) solvent ratios are given in volume:volume (v/v) terms; and

(xii) mass spectra (MS) were run with an electron energy of 70 electronvolts in the electron impact (EI) mode using a direct exposure probe;where indicated ionization was effected by chemical ionization (CI) orfast atom bombardment (FAB); values for m/z are given; generally, onlyions which indicate the parent mass are reported.

EXAMPLE 12-[2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-1-phenylimidazoleHydrochloride

A solution of n-butyl lithium (0.91 mL of a 2.44M solution in hexanes)in tetrahydrofuran (5 mL) was cooled to -78° C. and treated dropwisewith a solution of 1-phenylimidazole (0.320 g) in tetrahydrofuran (2mL). Upon complete addition, the resulting yellow solution was stirredat -78° C. for 30 minutes, then was treated dropwise with a solution ofN-methoxy-N-methyl-2-[(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)]butyramide(0.50 g) in tetrahydrofuran (5 mL). The resulting mixture was allowed towarm to room temperature and stirred for 16 hours. The reaction wasquenched by addition of saturated aqueous ammonium chloride andextracted with dichloromethane. The organic extract was washedsequentially with saturated aqueous ammonium chloride and brine, dried,filtered and evaporated to leave an orange oil. Purification bychromatography (65:35:10 dichloromethane:acetone:methanol) afforded thepure ketone (0.107 g), which was converted to the hydrochloride salt bytreatment with gaseous hydrogen chloride in diethyl ether. Thehydrochloride salt was prepared as a white powder; mp 128°-131° C.; NMR(CD₃ OD): 7.59 (d,1), 7.59-7.27 (m,12), 7.21 (m,2), 5.13 (t,1), 3.44(m,4), 3.15-2.95 (m,2), 2.60 (m,1), 2.24 (m,3), 1.95 (m,2); MS:m/z=536((M+H), ³⁷ Cl), 534((M+H), ³⁵ Cl). Analysis for C₃₀ H₂₉ Cl₂ N₃ O₂·1.0 HCl·0.5 H₂ O: Calculated: C, 62.13; H; 5.39; N, 7.25; Found: C,62.05; H, 5.10; N, 7.22.

The starting material2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)-N-methoxy-N-methylbutyramidewas prepared as follows.

a. Methyl 2-(3,4-dichlorophenyl)-4-pentenoate. A solution ofdiisopropylamine (12.75 g) in tetrahydrofuran was cooled to -10° C. andwas treated dropwise with a solution of n-butyllithium in hexanes (50 mLof a 2.44M solution). The resulting solution was cooled to -78° C. andwas treated dropwise with methyl 3,4-dichlorophenylacetate (25.0 g) toafford a deep yellow solution. To this solution was added1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (16.15 g) followed byallyl bromide (15.24 g). The reaction mixture was allowed to warm toroom temperature, was quenched by addition of saturated aqueous ammoniumchloride solution and extracted with ethyl acetate. The organic extractswere washed (saturated aqueous ammonium chloride, brine), dried, andevaporated to leave an amber oil. Purification by fractionaldistillation afforded the pentoate as a clear liquid (23.08 g); (bp125°-130° C., 1.1 Pa); NMR: 7.41 (d,1), 7.39 (d,1), 7.15 (dd,1), 5.65(m,1), 5.10-5.00 (m,3), 3.67 (s,3), 3.59 (m,1), 2.77(m,1), 2.48 (m,1).

b. 2-(3,4-Dichlorphenyl)-4-pentenoic acid. A solution of methyl2-(3,4-dichlorophenyl)-4-pentenoate (5.0 g) in methanol (100 mL) andtetrahydrofuran (100 mL) was treated with a solution of lithiumhydroxide monohydrate (4.05 g) in water (100 mL). The reaction wasstirred for 18 hours, then was evaporated, and the residue was dissolvedin water. The solution was acidified to pH ca. 2 by addition of 1Nhydrochloric acid and extracted with dichloromethane. The organicextracts were washed with brine, combined, dried, filtered andevaporated to yield the acid as a colorless syrup (4.61 g); NMR: 7.42(d,1), 7.40 (d,1), 7.12 (dd,1), 5.66 (m,1), 5.12-5.03 (m,2), 3.61 (t,1),2.78 (m,1), 2.50 (m,1); MS: m/z=247 ((M+H), ³⁷ Cl), 245 ((M+H), ³⁵ Cl).

c. 2-(3,4-Dichlorophenyl)-N-methoxy-N-methyl-4-pentenamide. A solutionof N,O-dimethylhydroxylamine hydrochloride (2.18 g) in dichloromethane(50 mL) was treated with triethylamine (5.65 g),2-(3,4-dichlorophenyl)-4-pentenoic acid (4.56 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.11 g) and4-dimethylaminopyridine (0.227 g). The resulting mixture was stirred for18 hours, was diluted with ethyl acetate and washed (water, 2Nhydrochloric acid, saturated aqueous sodium bicarbonate and brine). Theorganic extract was dried, and evaporated to leave a yellow syrup (5.31g). Chromatography, eluting with dichloromethane:methanol (95:5),afforded the amide as a colorless syrup (4.18 g); NMR: 7.46-7.16 (m,3),5.68 (m,1), 5.09-4.98 (m,2), 4.03 (broad t,1), 3.55 (s,3), 3.16 (s,3),2.78 (m,1), 2.42 (m,1); MS: m/z=290 ((M+H), ³⁷ Cl), 288 ((M+H), ³⁵ Cl).

d. 2-(3,4-Dichlorophenyl)-N-methoxy-N-methyl-4-oxobutyramide. A solutionof 2-(3,4-dichlorophenyl)-N-methoxy-N-methyl-4-pentenamide (4.00 g) indiethyl ether (40 mL), water (40 mL) and tetrahydrofuran (13 mL) wastreated with osmium tetraoxide (1.05 mL of a 0.2M solution in water) andsodium periodate (6.53 g), in portions over 20 minutes. The mixture wasstirred vigorously for 1.5 hours, a white precipitate of sodium iodateformed. The mixture was diluted with water and extracted with ethylacetate. The organic extract was washed (water, brine), dried, filteredthrough diatomaceous earth and silica gel and evaporated to leave thealdehyde as a dark amber syrup which was not purified further; NMR: 9.77(s,1), 7.41-7.13 (m,3), 4.50 (m,1), 3.65 (s,3), 3.49 (dd,1), 2.69(dd,1); MS: m/z=292((M+H), ³⁷ Cl), 290 ((M+H), ³⁵ Cl).

e.2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)-N-methoxy-N-methylbutyramide.A solution of 2-(3,4-dichlorophenyl)-N-methoxy-N-methyl-4-oxobutyramide(3.51 g), 4-hydroxy-4-phenylpiperidine (2.57 g) and glacial acetic acid(3 mL) in methanol (100 mL) was cooled to 0° C. and treated with sodiumcyanoborohydride (1.06 g), added in three equal portions. The reactionwas allowed to warm to room temperature and was stirred for 18 hours.The solvent was evaporated and the residue was dissolved indichloromethane, washed (1N aqueous sodium hydroxide, brine), dried, andevaporated to leave a brown foam (4.41 g). Chromatography, eluting withdichloromethane:methanol:ammonium hydroxide (950:50:1), afforded thealcohol as a pale amber syrup (2.76 g); NMR (CD₃ OD): 7.54-7.19 (m,8),4.19 (broad,1), 3.65 (s,3), 2.80 (broad s,3), 2.78 (m,2), 2.54-2.29(m,5), 2.11 (m,2), 1.91 (m,1), 1.73 (m,2); MS: m/z=453((M+H), ³⁷ Cl),451 ((M+H), ³⁵ Cl). A portion of the product was treated with etherealhydrogen chloride to afford the hydrochloride salt of thepiperidinobutyramide as a white powder, mp 108°-110° C.; Analysis forC₂₃ H₂₈ Cl₂ N₂ O₃ ·1.00 HCl·0.50 H₂ O: Calculated: C, 55.60; H, 6.09; N,5.64; Found: C, 55.60; H, 6.02; N, 5.59.

EXAMPLE 22-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-hydroxy-4-phenylpiperidino)butyl]-1-phenylimidazoleHydrochloride

A solution of2-[(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-1-phenylimidazole(0.191 g), prepared as described in Example 1, in methanol (5 mL) wascooled to 0° C. and treated with sodium borohydride (15 mg). Thereaction mixture was allowed to warm to room temperature and was stirredfor 4 hours. The solvent was evaporated and the residue was dissolved inethyl acetate, washed (water, brine) dried, filtered and evaporated toleave a white foam (0.167 g). Chromatography, eluting withdichloromethane:methanol:ammonium hydroxide (930:70:1), gave the titlecompound as a white foam (0.121 g). This product was treated withgaseous hydrogen chloride in diethyl ether to afford the hydrochloridesalt as a white powder (0.115 g); mp 161°-163.5° C.; NMR (CD₃ OD):7.60-7.24 (14), 6.93 (d,1), 5.24 (broad s,1), 3.44-3.20 (m,4), 3.19(m,1), 3.02 (m,1), 2.85 (m,1), 2.40-2.19 (m,4), 1.95 (m,2); MS:m/z=538((M+H), ³⁵ Cl), 536((M+H), ³⁵ Cl). Analysis for C₃₀ H₃₁ Cl₂ N₃ O₂·1.00 HCl·2.00 H₂ O: Calculated: C, 59.17; H, 5.96; N, 6.90; Found: C,59.10; H, 5.90; N, 6.86.

EXAMPLE 34-[2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-3-phenyl-1H-pyrazole

A solution of4-(3,4-dichlorophenyl)-6-(4-hydroxy-4-phenylpiperidino)-1-phenyl-hex-1-yne-3-one(0.30 g) in diethyI ether (25 mL) was cooled to 0° C. and was treatedwith diazomethane (generated by the reaction of and ethereal solution ofN-methyl-N-nitroso-p-toluenesulfonamide with ethanolic potassiumhydroxide (Anal. Chem., 45, 2302, 1973)). The resulting mixture wasallowed to warm to room temperature and stirred for 3 days. The solventwas evaporated. Radial chromatography, eluting withdichloromethane:methanol (gradient 97.5:2.5, 95:5), afforded the titlecompound (50 mg) as a white powder; mp 112°-114° C.; NMR: 8.13 (s,1),7.56-7.26 (m,12), 7.08 (d,1), 4.33 (broad s,1), 2.68 (m,2), 2.37 (m,3),2.05 (broad s,1), 1.86 (broad s,1), 1.73-1.43 (m,5); MS: m/z=534(M+l).Analysis for C₃₀ H₂₉ Cl₂ N₃ O₂ ·0.75 H₂ O: Calculated: C, 65.75; H,5.61; N, 7.67; Found: C, 65.71; H, 5.60; N, 7.83.

The starting material ketone was prepared as follows:

a.4-(3,4-Dichlorophenyl)-6-(4-hydroxy-4-phenylpiperidino)-1-phenylhex-1-yne-3-one.A solution of phenylacetylene (0.454 g) in tetrahydrofuran (8 mL) wascooled to -20° C. and treated with a solution of n-butyllithium inhexanes (1.91 mL of a 2.44M solution). The resulting dark mixture wasstirred at -20° C. for 15 minutes, then was cooled to -78° C. andtreated with a solution of2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)-N-methoxy-N-methylbutyramide(1.00 g), prepared as described in Example 1.e., in tetrahydrofuran (10mL). The mixture was stirred at -78° C. for 2 hours, was warmed to -30°C. and quenched with saturated aqueous ammonium chloride solution. Themixture was extracted with ethyl acetate. The organic extracts werewashed (brine) dried, and evaporated to leave a pale green syrup.Chromatography, eluting with hexane:ethyl acetate (20:80), afforded theketone as a pale amber foam (0.703 g). A portion of this product wasconverted to the corresponding hydrochloride salt for characterizationby treatment with ethereal hydrogen chloride to give a white powder; mp99°-101° C.; Analysis for C₂₉ H₂₇ Cl₂ NO₂ ·0.5 H₂ O·1.0 HCl: Calculated:C, 64.75; H, 5.43; N, 2.60; Found: C, 64.73; H, 5.32; N, 2.56.

EXAMPLE 43-[2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-4-phenyl-1H-pyrazole

The crude material isolated in Example 3, was purified by radialchromatography to afford the title compound as a white powder; mp108°-110° C.; NMR: 7.63 (s,1), 7.50-7.25 (m,12), 7.08 (broad d,1), 4.71(broad s,1), 2.76 (m,2), 2.54-2.44 (m,4), 2.15-1.72 (m,3), 1.53 (m,2),1.43 (broad s,1); MS: m/z=534 (M+1). Analysis for C₃₀ H₂₉ Cl₂ N₃ O₂ ·0.5H₂ O: Calculated: C, 66.30; H, 5.56; N, 7.73; Found: C, 66.31; H, 5.55;N, 7.74.

EXAMPLE 54-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-hydroxy-4-phenylpiperidino)butyl]-3-phenyl-1H-pyrazole

A solution of4-[2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-3-phenyl-1H-pyrazole(95 mg), prepared as described in Example 3, in methanol (3 mL) wascooled to 0° C. and treated with sodium borohydride (9 mg). The mixturewas allowed to warm to room temperature and was stirred for 1 hour. Thesolvent was evaporated and the residue partitioned between water andethyl acetate. The organic extracts were washed (water, brine) combined,dried, and evaporated to afford a white foam. Trituration withether:hexane (1:2) afforded the title compound as a white solid (62 mg);mp 133°-135° C.; NMR: 7.57-7.23 (m,13), 7.03 (m,1), 5.11 (d,1), 3.04(m,1), 2.86 (m,2), 2.51 (m,2), 2.37 (m,2), 2.23 (m,2), 1.94 (m,1),1.81-1.60 (m,3); MS: m/z=536(M+1). Analysis for C₃₀ H₃₁ Cl₂ N₃ O₂ ·1.00H₂ O: Calculated: C, 64.98; H, 5.82; N, 7.83; Found: C, 64.91; H, 5.74;N, 7.53.

EXAMPLE 63-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-hydroxy-4-phenylpiperidino)butyl]-4-phenyl-1H-pyrazole

By a procedure similar to that described in Example 5, except using5-[2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-4-phenyl-1H-pyrazole,the title compound was obtained as a white powder; mp 122°-124° C.; NMR:7.52 (m,2), 7.43-7.18 (m,8), 7.10 (m,2), 6.88 (d,1), 5.40 (m,1), 3.10(m,1), 2.95 (m,2), 2.70-2.48 (broad m,2), 2.43 (m,2), 2.24 (m,2),1.98-1.78 (broad m,3), 1.55 (m,1); MS: m/z=536(M+1). Analysis for C₃₀H₃₁ Cl₂ N₃ O₂ ·0.25 H₂ O: Calculated: C, 66.60; H, 5.87; N, 7.77; Found:C, 66.39; H, 5.86; N, 7.67.

EXAMPLE 75-[(1S,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyl]-1-phenylpyrazoleCitrate Salt

A solution of5-[(1S,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazole(89 mg) and 4-hydroxy-4-phenylpiperdine (41 mg) in methanol was adjustedto pH=5.5 by addition of glacial acetic acid. The resulting mixture wastreated with sodium cyanoborohydride (15 mg) and stirred for 2 hours.The solvent was evaporated and the residue was partitioned between 1Naqueous sodium hydroxide and dichloromethane. The organic extracts werewashed (brine) dried, filtered and evaporated to leave an off-white foam(110 mg). Purification by chromatography (100:2.5:0.1chloroform/methanol/ammonium hydroxide) afforded the title compound(77.5 mg) as a white foam. The citrate salt was prepared by treatment ofthis material with citric acid in diethyl ether/methanol (10:1). mp112°-117° C.; NMR: 7.66 (d, 1, J=1.7), 7.50-7.22 (m,12), 7.04 (dd, 1,J=1.7, 8.4), 6.41 (d, 1, J=1.7), 6.03 (d, 1, J=6.6), 5.18 (broad, 1),3.34 (broad m), 2.60 (q, J=14.0) Hz, citrate), 2.00 (broad m), 1.94(s,3), 1.71 (m,2); MS: m/z=606 ((M+1+28), 13%), 582 (12), 581 (15), 580((M+1), 37Cl, 58), 579 (24), 578 ((M+1), 35Cl, 86), 562 (25), 560 (36),520 (38), 518 (54). Analysis for C₃₂ H₃₃ Cl₂ N₃ O₃ ·1.00 C₆ H₈ O₇ ·0.7H₂ O: Calculated C, 58.27; H, 5.46; N, 5.36; Found: C, 58.36; H, 5.60;N, 5.23.

The starting material5-[(1S,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazolewas prepared as follows:

a. (S)-2-(3,4-Dichlorophenyl)-4-pentenoic acid. A solution of2-(3,4-dichlorophenyl)-4-pentenoic acid (24.2 g), in ethyl acetate (100mL) was treated with a solution of (S)-(α)-methylbenzylamine (12.1 g) inethyl acetate (100 mL). The resulting crystalline enricheddiastereomeric salt was isolated by filtration. The enricheddiastereomeric salt was recrystallized five times from ethyl acetate(150 mL, 150 mL, 100 mL, 100 mL, 75 mL) to afford highly enriched salt(6.13 g, 17%, diastereomeric ratio 95:5 as determined by HPLC). Thissalt was dissolved in water (25 mL) and the resulting solution wasacidified to pH 2-3 with 2.5N hydrochloric acid and then extracted withethyl acetate (2×100 mL). The organic extracts were washed (water)dried, filtered and evaporated to afford the optically enriched acid asa clear oil (3.87 g); [α]_(D) =+54.1 (C=3.43, methanol).

HPLC analysis: Column Ultron Ovomucoid (ES-OVM) 15 cm×6 mm; Eluent: 30%acetonitrile/70% aqueous KH₂ PO₄ buffer (10 mM) adjusted to pH 5.5 with1M potassium hydroxide; Flow 1 mL/min; Wavelength: 230 nm; Retentiontimes: (S) enantiomer 4.11 min., (R) enantiomer 5.91 min.

b. (S)-2-(3,4-Dichlorophenyl)-N-methoxy-N-methyl-4-pentenamide. Using aprocedure similar to that described in Example 1.c., except using(S)-2-(3,4-dichlorophenyl)-4-pentenoic acid, the amide was prepared as apale amber oil (75%); NMR: 7.43 (d,1), 7.37 (d, 1), 7.17 (dd, 1), 5.68(m,1), 5.02 (m,2), 4.03 (broad t,1), 2.77 (m,1), 2.40 (m,1).

c. 5-((S)-2-(3,4-Dichlorophenyl)-4-pentenoyl)-1-phenylpyrazole.Lanthanum (III) chloride heptahydrate (830 mg) was dried in vacuo (140°C.; 0.2 torr) for 2 hours, was cooled to room temperature under nitrogenand suspended in dry tetrahydrofuran (5 mL). The suspension was stirredfor 24 hours at room temperature. In a separate flask, a solution of1-phenylpyrazole in tetrahydrofuran (4 mL) was cooled to -30° C. andtreated dropwise with n-butyllithium (0.84 mL of a 2.48M solution inhexanes). The resulting tan suspension was warmed to room temperatureand was stirred for 0.5 hours. The lanthanum chloride/tetrahydrofuransuspension was cooled to -78° C. and treated with the5-lithiol-1-phenylpyrazole solution, transferred via cannula. Theresulting suspension was stirred at -78° C. for 0.25 hours, and wastreated with a solution of(S)-2-(3,4-dichlorophenyl)-N-methoxy-N-methyl-4-pentenamide (450 mg) intetrahydrofuran (5 mL). The reaction mixture was stirred at -78° C. for1 hour, was slowly warmed to 0° C. and quenched by addition of aqueousacetic acid (5 mL, 1%). The mixture was poured into aqueous acetic acid(50 mL, 1%) and extracted with ethyl acetate). The organic extracts werewashed (brine) dried, and evaporated to leave an amber oil (640 mg).This oil was purified by radial chromatography (2 mm SiO2, 8:1hexane/ethyl acetate, 4:1 hexane/ethyl acetate, 1:1 hexane/ethylacetate) to afford the title compound as a colorless oil (310 mg); NMR:7.66 (d,1), 7.47-7.21 (m,7), 7.11 (dd,1), 6.96 (d,1), 5.65 (m,1), 5.02(m,2), 4.30 (t,1), 2.83 (m,1), 2.46 (m,1).

5-[(1S,2S)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenylpyrazole.A solution of5-((S)-2-(3,4-dichlorophenyl)-4-pentenoyl)-1-phenylpyrazole (130 mg) inmethanol (5 mL) was cooled to 0° C. and treated with sodium borohydride(20 mg). The resulting mixture was stirred for 0.25 hours, wasevaporated. The residue was partitioned between water and ethyl acetate(2×). The organic extracts were washed (brine) combined, filtered andevaporated to leave the alcohol as a white foam (118 mg). NMR showedthis material to be about 95% the (1S,2S) diastereomer; NMR: 7.61 (d,1),7.53-7.15 (m,7), 6.90 (dd,1), 6.28 (d,1), 5.36 (m,1), 4.85 (m,3), 2.90(m,1), 2.38-2.04 (m,2). Analysis of this material by HPLC on a chiralstationary phase showed it to have the following composition: 86.5%(1S,2S), retention time=18.1 min 7.5% (1R,2S), retention time=13.7 min5.4% (1R,2R), retention time=16.8 min 0.5% (1S, 2R). retention time=15.3min Analysis conditions: Column: 4.6 mm×25 cm Chiralcel OD Eluent: 90:10hexane/isopropanol Flow rate: 0.8 mL/min Detection: uv @215 nM, 0.2 AUFS

e.5-[(1S,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenylpyrazole.Asolution of5-[(1S,2S)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenylpyrazole(110 mg) in dichloromethane (2 mL) was treated with triethylamine (35mg), acetic anhydride (36 mg) and 4-N,N-dimethylaminopyridine (3 mg).The resulting mixture was stirred at room temperature for 0.5h, waspoured into 1N hydrochloric acid (10 mL) and extracted with ethylacetate (2×). The organic extracts were washed with 10% (w/v) aqueoussodium bicarbonate and brined, combined, dried, filtered and evaporatedto give the acetoxy compound as a clear oil (92 mg), which was usedwithout purification; MS: m/z=417 ((M+1), 37Cl), 415((M+1), 35Cl).

f.5-[(1S,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazole.Asolution of5-[(1S,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenylpyrazole(90 mg) in tetrahydrofuran (1 mL), diethyl ether (2 mL) and water (2 mL)was treated with osmium tetraoxide (0.07 mL of a 0.2M solution in water)and sodium periodate (100 mg). The resulting biphasic mixture wasstirred vigorously at room temperature for 4 hours. The mixture wasdiluted with water and extracted with ethyl acetate. The organicextracts were washed (brine), dried, and evaporated to afford the titlecompound as a pale amber foam (89 mg). This material was usedimmediately; NMR: 9.57 (s,1), 7.62 (d,1), 7.45-7.21 (m,6), 6.99 (d,1),6.72 (dd,1), 6.31 (d,1), 6.15 (d,1), 3.63 (m,1), 2.77 (m,2), 2.03 (s,3);MS: m/z=419((M+1), 37Cl), 417((M+1), 35Cl).

EXAMPLE 84-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-hydroxy-4-phenylpiperidino)butyl]-5-phenyl-(1H)-1,2,3-triazoleBishydrochloride

Using a procedure similar to that described in Example 2, except using5-[2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-4-phenyl-(1H)-1,2,3-triazole,the title hydrochloride salt was obtained as a white powder; mp153°-155° C.; NFER (d₄ MeOH): 7.50-7.20 (broad m,12), 6.99 (m,1), 5.24(d,1), 5.07 (d,1), 3.52-3.20 (broad m,6), 2.91 (m,1), 2.32-2.02 (broadm,4), 1.96 (m,2); MS: m/z=539 ((M+1), 37Cl), 537 ((M+1), 35Cl). Analysisfor C₂₉ H₃₀ Cl₂ N₄ O₂ ·2.00 HCl·2.5 H₂ O: Calculated C, 53.14; H, 5.68;N, 8.54; Found: C, 53.14; H, 5.40; N, 8.52. Found C: 53.14; H: 5.40; N:8.52

The starting material5-[2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenyl-piperidino)butyroyl]-4-phenyl-(1H)-1,2,3-triazolewas prepared as follows:

a.4-(3,4-Dichlorophenyl)-6-(4-hydroxy-4-phenylpiperidino)-1-phenyl-1-hexyn-3-one.A solution of phenylacetylene (454 mg) in tetrahydrofuran (8 mL) wascooled to -20° C. and was treated with n-butyllithium (1.91 mL of a2.44M solution in hexanes). This mixture was stirred at -20° C. for 0.25hours, was cooled to -78° C. and was treated with a solution of2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)-N-methoxy-N-methylbutyramide(1.00 g), prepared as described in Example 1.e., in tetrahydrofuran (10mL). The reaction mixture was stirred at -78° C. for 2 hours, warmed to-30° C., quenched by addition of saturated aqueous ammonium chloride andextracted with ethyl acetate. The organic extracts were washed(saturated aqueous ammonium chloride, brine), dried, and evaporated toleave a green syrup (1.12 g). Chromatography, eluting with hexane:ethylacetate (80:20) afforded the acetylene (703 mg) as a tan foam; A sample(100 mg) of this product was converted to the hydrochloride salt withhydrogen chloride (g) in diethyl ether, and isolated as a tan powder; mp99°-100° C.; NMR (d4-MeOH): 7.65-7.25 (m,13), 4.11 (5,1), 3.64-3.31(m,5), 3.07 (m,1), 2.68 (m,1), 2.30 (m,3), 1.98 (m,2); MS: m/z=494((M+1), 37Cl), 492 ((M+1), 35Cl). Analysis for C₂₉ H₂₇ Cl₂ NO₂ ·1.0HCl·0.5 H₂ O: Calculated C, 64.75; H, 5.43; N, 2.60; Found: C, 64.72; H,5.32; N, 2.56.

b.5-[2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyroyl]-4-phenyl-(1H)-1,2,3-triazole.A suspension of sodium azide (38 mg) in N,N-dimethylformamide (1 mL) wastreated dropwise with a solution of4-(3,4-dichlorophenyl)-6-(4-hydroxy-4-phenyl-piperidino)-1-phenyl-1-hexyn-3-one(287 mg) in N,N-dimethylformamide (4 mL). The reaction mixture waswarmed to 35° C. and was stirred for 3 hours. The reaction was quenchedby addition of water and extracted with ethyl acetate. The organicextracts were combined, washed (water, brine) and evaporated to leave anorange syrup. The syrup was triturated with dichloromethane to affordthe triazole as a pale tan powder (260 mg, 83%). NMR (d6-DMSO): 7.89(m,2), 7.63 (d, J=1.8 Hz, 1), 7.57 (d, J=8.3 Hz, 1), 7.45-7.17 (m,9),5.24 (t, J=7.3 Hz, 1H, H-C(2')), 4.91 (broad s, 1H, O), 2.86-2.50 (m,7),1.95-1.49 (m,5H).

EXAMPLE 95-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyl]-1-phenylpyrazoleCitrate Salt

Using a procedure similar to that described in Example 7, except using5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazoleas the aldehyde component in the reductive alkylation, the citrate saltof the title compound was prepared as a white powder (43%); mp 93°-95°C.; NMR (d4-MeOH): 7.60 (d,1), 7.50-7.32 (m,6), 7.24 (m,3), 7.15 (m,2),7.10 (s,1), 6.73 (d,1), 6.60 (d,1), 5.88 (d,1), 3.36 (m,2), 3.20 (m,2),3.07 (m,1), 2.86-2.71 (q, citrate), 2.45 (m,1), 2.32 (m,2), 2.18 (s,3),1.86 (broad d, 2); MS: m/z=580((M+1), 37Cl), 578 ((M+1), 35Cl). Analysisfor C₃₂ H₃₂ Cl₂ N₃ O₃ ·1.0 C₆ H₈ O₇ ·1.5 H₂ O: Calculated C, 57.22; H,5.56; N, 5.27; Found: C, 57.22; H, 5.41; N, 4.91.

The starting material aldehyde was prepared as follows.

a. 2-(3,4-Dichlorophenyl)-4-pentenol. A suspension of lithium aluminumhydride (1.65 g) in diethyl ether (25 mL) was cooled to 0° C. and wastreated dropwise with a solution of methyl2-(3,4-dichlorophenyl)-4-pentenoate (7.50 g), prepared as described inExample 1.a., in diethyl ether (75 mL). The reaction mixture was stirredat 0° C. for 2 hours, was warmed to room temperature and stirred for 1hour. The mixture was cooled to 0° C. and quenched by addition ofsaturated aqueous sodium sulfate solution (10 mL). The mixture waspartitioned between water and diethyl ether (3×). The organic extractswere combined, washed (water, brine) dried, and evaporated to afford thetitle compound as a clear oil (6.69 g, 94%); NMR: 7.40 (d,1), 7.32(d,1), 7.05 (dd,1), 5.65 (m,1), 4.99 (m,1), 3.87-3.71 (m,3), 2.84 (m,1),2.51-2.31 (broad m,2).

b. 2-(3,4-Dichlorophenyl)-4-pentenal. A solution of oxalyl chloride(6.85 g) in dichloromethane (35 mL) was cooled to -78° C. and wastreated dropwise with dimethyl sulfoxide (4.64 g) in dichloromethane (10mL). The resulting solution was stirred at -78° C. for 0.5 hours, wastreated with a solution of 2-(3,4-dichlorophenyl)-4-pentenol (6.24 g) indichloromethane (50 mL). The reaction mixture was stirred at -78° C. for2 hours, was treated with triethylamine (13.66 g). The mixture wasallowed to warm to room temperature and was stirred for 1 hour. Themixture was diluted with dichloromethane (250 mL), washed (water,brine),dried, and evaporated to afford the aldehyde as a pale yellow oil (6.35g) which was used without purification in the next step; MS:m/z=231((M+1), 37Cl), 229((M+1), 35Cl).

c.5-((1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-pentenyl)-1-phenylpyrazole.Cerium (III) chloride heptahydrate (9.70 g) was dried at 140° C. at 0.2torr for 2 hours, and was cooled to room temperature and suspended intetrahydrofuran (100 mL). The suspension was stirred at room temperaturefor 2 hours. In a separate flask, a solution of n-butyllithium (9.14 mLof a 2.44M solution in hexanes) in tetrahydrofuran (40 mL) was cooled to-30° C. and was treated with a solution of 1-phenylpyrazole (3.22 g) intetrahydrofuran (10 mL). The resulting orange solution was warmed toroom temperature, stirred for 0.5 hours, and added to the cooled (-78°C.) cerium chloride/tetrahydrofuran suspension. The resulting orangesuspension was stirred at -78° C. for 0.5 hours and treated with asolution of 2-(3,4-dichlorophenyl)-4-pentenal (4.26 g) intetrahydrofuran (30 mL). The reaction mixture was allowed to warm to 0°C., was stirred at 0° C. for 1 hour and quenched by addition of aqueousacetic acid (1%). The mixture was poured into aqueous acetic acid (100mL, 1%) and extracted with ethyl acetate. The organic extract was washed(aqueous acetic acid (1%), brine), dried, and evaporated to leave anorange oil (8.45 g). Chromatography, eluting with hexane:ethyl acetate(80:20), afforded the title compound (2.35 g) as a pale amber oil, alongwith fractions containing the title compound mixed with the (1RS,2RS)diastereomer (2.20 g). Further purification of these mixed fractions byradial chromatography (4 mm SiO2, 97:3 dichloromethane/methanol)afforded additional (1RS,2SR) compound (0.22 g) as a pale amber oil;NMR: 7.54 (d,1), 7.49-7.15 (m,6), 6.86 (d,1), 6.62 (dd,1), 6.27 (d,1),5.45 (m,1), 4.93-4.81 (m,3), 2.91 (m,1), 2.71 (m,1), 2.33 (m,1).

d.5-((1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl)-1-phenylpyrazole.Using a procedure similar to that described in Example 7.e., exceptusing5-((1RS,2SR)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl)-1-phenylpyrazole,the title compound was prepared as a white foam (73%); NMR: 7.56 (d, 1),7.46-7.02 (m,6), 6.75 (d,1), 6.48 (dd,1), 6.40 (d,1), 5.96 (d,1), 5.39(m,1), 4.89 (m,2), 2.96 (m,1), 2.60 (m,1), 2.32 (m,1), 2.14 (s,3).

e.5-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazole.Using a procedure similar to that described in Example 7.f., exceptusing5-((1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl)-1-phenylpyrazole,the aldehyde was prepared as a white foam (89%); MS: m/z=419((M+1),37Cl), 417((M+1), 35Cl).

EXAMPLE 105-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-hydroxy-4-phenylpiperidino)butyl]-1-phenylpyrazoleCitrate Salt

A solution of5-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyl]-1-phenylpyrazole(150 mg), prepared as described in Example 9, in methanol (5 mL) wastreated with a solution of lithium hydroxide monohydrate (22 mg) inwater (0.6 mL). The resulting mixture was stirred at room temperaturefor 16 hours, was adjusted to pH=3 by addition of 1N hydrochloric acid.The solvents were evaporated and the residue was purified bychromatography, eluting with dichloromethane:methanol:ammonium hydroxide(95:5:0.1) to leave an off white foam (115 mg). This product wasdissolved in diethyl ether (25 mL) and was treated with a solution ofcitric acid (0.5 N in methanol) to afford the title compound (98 mg) asa white powder; mp 127°-130° C.; NMR (d4-MeOH): 7.55-7.24 (broad m,11),7.12 (d,1), 6.81(s,1), 6.60 (d,1), 6.39 (s,1), 4.84 (d,1), 3.06-2.83(broad m,3), 2.78 (m,1), 2.53 (m,3), 2.39-2.18 (broad m,2), 2.10 (m,1),1.85 (m,3); MS: m/z=538((M+1), 37Cl), 536((M+1), 35Cl). Analysis for C₃₀H₃₁ Cl₂ N₃ O2·1.00 C₆ H₈ O₇ : Calculated C, 59.34; H, 5.40; N, 5.77;Found: C, 59.70; H, 5.47; N, 5.83.

EXAMPLE 115-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazoleCitrate Salt

Using a procedure similar to that described in Example 7, except using4-acetamido-4-phenylpiperidine as the piperidine component, and5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazoleas the aldehyde component, the title compound was prepared as thecitrate salt (58%); mp 112°-115° C.; NMR (d4-MeOH): 8.19 (s,1), 7.61(d,1), 7.44-7.36 (m,6), 7.25 (m,3), 7.12 (m,2), 7.00 (s,1), 6.74 (d,1),6.62 (d,1), 5.90 (d,1), 3.34 (m,2), 3.19 (m,1), 2.89-2.73 (m,2), 2.89(q,4), 2.64 (m,3), 2.45 (m,1), 2.19 (s,3), 2.38-2.08 (m,4), 1.98 (s,3);MS: m/z=621((M+1), 37Cl), 619((M+1), 35Cl). Analysis for C₃₄ H₃₆ Cl₂ N₄O₃ ·1.25 C₆ H₈ O₇ ·1.0 H₂ O: Calculated C, 56.78; H, 5.51; N, 6.38;Found C, 57.13; H, 5.55; N, 5.98.

The starting material 4-acetamido-4-phenylpiperidine was prepared asfollows.

a. 4-Hydroxy-4-phenyl-1-trifluoroacetylpiperidine. To a suspension of4-hydroxy-4-phenylpiperidine (20 g) in dichloromethane (100 mL) wasadded ethyl trifluoroacetate (14.8 mL). Acetonitrile (50 mL) was addedas a co-solvent, and the solution was stirred overnight. The mixture waswashed (aqueous sodium bicarbonate), and the separated organic phase wasdried and evaporated to give the trifluoromethylacetyl compound as ayellow solid; MS: m/z=274(M+1). p b.4-Azido-4-phenyl-1-trifluoroacetylpiperidine. To a suspension of sodiumazide (9.5 g) in chloroform (100 mL) and trifluoroacetic acid (115 mL)cooled to 0° C. was added the above piperidine (20 g) in chloroform (100mL) dropwise over a period of 1 hour. The mixture was allowed to warm toambient temperature gradually and stirred overnight. After evaporatingthe chloroform and trifluoroacetic acid, the resulting mixture wasdiluted with aqueous sodium bicarbonate and extracted withdichloromethane. The organic extracts were dried and evaporated to givethe azido piperidine as a viscous oil (20 g); NMR: 7.41 (m,5), 4.51(m,1), 3.97 (m,1), 3.61 (m,1), 3.26 (m,1), 2.10 (m,4); MS: m/z=299(M+1).

c. 4-Amino-4-phenyl-1-trifluoroacetylpiperidine andN-[4-Phenyl-1-(2,2,2-trifluoroacetyl)piperidin-4-yl] acetamide. Asolution of the above azide (15 g) and 20% palladium hydroxide on carbon(1.5 g) in ethanol (150 mL) was stirred overnight under 1 barr ofhydrogen. The reaction mixture was filtered through diatomaceous earthand the filtrate was concentrated in vacuo. The resulting oil wasdissolved in dichloromethane and extracted with dilute aqueoushydrochloric acid. The acidic aqueous phase was extracted two times withdichloromethane (discarded), neutralized with saturated aqueous sodiumbicarbonate, and extracted with dichloromethane. The organic extractswere dried and evaporated to give the amine; NMR (CD₃ OD): 7.34 (m,5),3.17 (m,1), 3.04 (m,1), 2.64 (m,1), 2.15 (m,1).

d. 4-Acetamido-4-phenyl-1-trifluoroacetylpiperidine. To the above aminein dichloromethane (80 mL) was added acetic anhydride (1.6 mL) andtriethylamine (2.5 mL). The mixture was stirred overnight, washed,(dilute hydrochloric acid, dilute aqueous sodium bicarbonate), dried andevaporated to give the acetamide as a white solid (13.0 g); NMR: 7.30(m,5), 6.08 (s,1), 4.24 (m,1), 3.82 (m,1), 3.48 (m,1), 3.23 (m,1), 2.65(m,1), 2.42 (m,1), 2.09 (m,2), 2.00 (s,3); MS: m/z=315(M+1).

e. 4-Acetamido-4-phenylpiperidine. To a solution of the above acetamide(13.0 g) in methanol (120 mL) was added lithium hydroxide monohydrate(5.2 g) in water (30 mL). After being stirred for 3 hours, the mixturewas evaporated, diluted with water, and extracted with dichloromethane.The aqueous layer was saturated with sodium chloride and extracted withethyl acetate. The combined organic extracts were dried and evaporatedto give the deprotected piperidine as a white solid (2.5 g) byprecipitation from acetonitrile; NMR (CD₃ OD): 7.29 (m,5), 2.98 (m,4),2.44 (m,2), 1.97 (m,5); NMR (CD₃ OD/CF₃ COOH): 7.31 (m,5), 3.28 (m,4),2.68 (m,2), 2.18 (m,2), 2.02 (s,3); MS: m/z=219(M+1).

EXAMPLE 125-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-(N-acetylamino)-4-phenylpiperidino)butyl]-1-phenylpyrazole

Using a procedure similar to that described in Example 10, except using5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazole,the title compound was prepared as a white powder (54%); mp 115°-118°C.; NMR: 7.51 (s,1), 7.45-7.32 (broad m,6), 7.27 (m,4), 7.21 (d,1), 6.80(s,1), 6.58 (d,1), 6.37 (s,1), 5.49 (s,1), 4.82 (d,1), 2.94 (m,2), 2.81(m,1), 2.54-2.41 (broad m,5), 2.28 (broad m,3), 2.01 (broad s,4), 1.85(m,1); MS: m/z=579((M+1), 37Cl), 577((M+1), 35Cl).

EXAMPLE 135-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(4-(1-ethyl-1-hydroxypropyl)piperidino)butyl]-1-phenylpyrazoleCitrate Salt

Using a procedure similar to that described in Example 7, except using4-(1-ethyl-1-hydroxypropyl)piperidine, as the amine component, and5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazoleas the aldehyde component, the title compound was prepared as thecitrate salt (53%); mp 76°-79° C.; NMR (d4-MeOH): 7.61 (d,1), 7.61-7.36(m,3), 7.21 (d,1), 7.12 (m,2), 6.97 (s,1), 6.71 (d,1), 6.61 (d,), 5.89(d, 1), 3.47 (m,2), 3.25 (m,1), 2.91-2.72 (m,4), 2.91 (m,4), 2.55-2.45(broad m,2), 2.19 (s,3), 1.85 (broad s,2), 1.56 (broad s,3), 1.51 (m,4);MS: m/z=574 ((M+1), 37Cl), 572((M+1), 35Cl). Analysis for C₃₁ H₃₉ Cl₂ N₃O₃ ·1.00 C6H8O7·1.5 H₂ O; Calculated: C, 56.13; H, 6.37; N, 5.31; FoundC, 56.44; H, 6.24; N, 4.94.

The starting material 4-(1-ethyl-1-hydroxypropyl)piperidine was preparedas follows.

a. Ethyl 1-(benzyloxycarbonyl)-4-piperidine carboxylate. A solution ofethyl 4-piperidine carboxylate (14.71 g) and triethylamine (12.04 g) inchloroform (200 mL) was cooled to 0° C. and treated dropwise with benzylchloroformate (17.91 g). The resulting mixture was stirred at 0° C. for1 hour, was allowed to warm to room temperature and was stirred for 12hours. The mixture was washed (brine, 1N hydrochloric acid), dried, andevaporated to yield a pale yellow oil (26.4 g). Chromatography, elutingwith dichloromethane:methanol (95:5) gave the benzyl compound as acolorless syrup (22.15 g); NMR: 7.35 (m,5, 5.07 (s,2), 4.06 (q,2), 3.91(broad d,2), 2.95 (broad, 2), 2.53 (m,1), 1.82 (broad d,2), 1.41 (m,2),1.18 (t,3).

b. 1-(Benzyloxycarbonyl)-4-(1-ethyl-1-hydroxypropyl)piperdine. Asolution of ethyl magnesium chloride (10.7 mL of a 2M solution intetrahydrofuran) in tetrahydrofuran (25 mL) was cooled to -60° C. andtreated dropwise with a solution of ethyl1-(benzyloxycarbonyl)-4-piperidine carboxylate (2.50 g) intetrahydrofuran (10 mL). The resulting solution was stirred at -60° C.for 1 hour, was warmed to 0° C. for 1 hour, quenched by addition of 1Nhydrochloric acid, diluted with water and extracted with ethyl acetate.The organic extracts were washed (brine, 1N hydrochloric acid), dried,and evaporated to afford the title compound as a colorless oil (2.49 g).This material was used without purification in the next step; NMR: 7.35(m,5), 5.12 (s,2), 4.27 (m,2), 2.71 (broad, 2), 1.67-1.29 (m,10), 0.86(t,6).

c. 4-(1-Ethyl-1-hydroxypropyl)piperidine. A solution of1-(benzyloxycarbonyl)-4-(1-ethyl-1-hydroxypropyl)piperidine (2.44 g) inethanol (50 mL) was hydrogenated over 10% palladium on carbon (100 mg,3.45 bar) for 4 hours. The mixture was filtered and evaporated to affordthe piperidine as a clear oil which solidified upon standing (1.37 g);NMR: 3.26 (broad d,2), 2.69 (m,2), 1.71 (broad d,2), 1.60-1.39 (m,7),0.86 (t,6)

EXAMPLE 145-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-(1-ethyl-1-hydroxypropyl)piperidino)butyl]-1-phenylpyrazoleCitrate Salt

Using a procedure similar to that described in Example 10, except using5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-(1-ethyl-1-hydroxypropyl)piperidino)butyl]-1-phenylpyrazole,the title compound was prepared as a white powder (54%); mp 80°-83° C.;NMR (d4-MeOH): 7.57 (s 1), 7.47 (m,3), 7.22 (d,1), 7.08 (m,2), 7.01(s,1), 6.78 (d,1), 6.60 (s,1), 4.75 (d,1), 3.50(m,2), 2.95 (m,3),2.83-2.59 (broad m,4), 2.00 (broad s,1), 1.86 (broad s,2), 1.58 (broads,2), 1.48(m,4), 0.85 (t,6); MS: m/z=532 ((M+1), 37Cl), 530((M+1),35Cl). Analysis for C₂₉ H₃₇ Cl₂ N₃ O₂ ·1.00 C₆ H₈ O₇ ·0.75 H₂ O:Calculated: C, 57.10; H, 6.37; N, 5.71; Found: C, 57.14; H, 6.28; N,5.48.

EXAMPLE 155-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenyl-1,2,3-(1H)triazole

Using a procedure similar to that described in Example 10, except using5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole,the title compound was prepared as a light tan powder (78%); mp125°-128° C.; NMR: 7.72 (s,1), 7.50-7.23 (broad m,10), 7.12 (d,1), 6.80(s,1), 6.56 (d,1), 5.57 (s,1), 4.85 (d,1), 2.93-2.66 (broad m,3),2.60-2.22 (broad m,8), 2.02 (s,4), 1.86 (broad d,1); MS: m/z=580((M+1),37Cl), 578((M+1), 35Cl). Analysis for C₃₁ H₃₃ Cl₂ N₅ O₂ ·0.5 H₂ O;Calculated: C, 63.37; H, 5.83; N, 11.92; Found: C, 63.51; H, 5.76; N,11.56.

The starting material5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared as follows:

a. 1-Phenyl-4-trimethylsilyl-1,2,3-triazole. A solution of phenyl azide(2.10 g, 20% in hexane) and trimethylsilylacetylene (5.18 g) in hexane(35 mL) was heated to 50° C. for 3 days. The mixture was cooled to roomtemperature and the resulting crystals were isolated by filtration andwas washed with cold hexane to give1-phenyl-4-trimethylsilyl-1,2,3-triazole (46%); NMR: 7.94 (s,1), 7.74(m,2), 7.54-7.26 (m,3), 0.38 (s,9).

b. 1-Phenyl-1,2,3-triazole. A solution of1-phenyl-4-trimethylsilyl-1,2,3-triazole (1.76 g) in 10% (w/v) aqueouspotassium hydroxide was treated with tetrabutylammonium fluoride (2 mg)at 50° C. for 16 hours. An additional quantity (10 mg) oftetrabutylammonium fluoride was added, and the reaction continued for anadditional 24 hours at 50° C.; The cooled reaction mixture was partitionbetween diethyl ether and water. The organic extract was washed (water,brine) dried, and evaporated to leave a white foam. crystallization fromdiethyl ether:hexane (1:2) gave the title compound as an off white solid(970 mg); NMR: 8.00 (d,1), 7.86 (d,1), 7.74 (m,2), 7.57-7.26 (m,3).

c.5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.Using a procedure similar to that described in Example 9.c., exceptusing 1-phenyl-1,2,3-triazole in the lithiation reaction at -50° C., thealcohol was prepared as a pale amber syrup (17%); NMR: 7.71 (s,1),7.54-7.50 (m,3), 7.26-7.17 (m,3), 6.85 (d,1), 6.62 (dd,1), 5.44 (m,1),4.94-4.90 (m,3), 2.92 (m,2), 2.74 (m,1), 2.38 (m,1).

d.5-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.Using a procedure similar to that described in Example 7.e., exceptusing5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazoleand purifying by radial chromatography (2 mm SiO275:25 hexane/ethylacetate), the acetate was prepared as a colorless glass (61%); NMR: 7.75(s,1), 7.47 (m,3), 7.18 (m,2), 7.09 (d,1), 6.76 (d,1), 6.49 (dd,1), 5.92(d,1), 5.38 (m,1), 4.91 (m,2), 3.00 (m,1), 2.70 (m,1), 2.32 (m,1), 2.16(s,3).

e.5-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole.Using a procedure similar to that described in Example 7.f., exceptusing5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole,the aldehyde was prepared as a white foam which was used withoutpurification in the next step; MS: m/z=420((M+1), 37Cl), 418((M+1),35Cl).

f.5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole.Using a procedure similar to that described in Example 7, except using4-acetamido-4-phenylpiperidine as the amine component, and5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazoleas the aldehyde component, the coupling product was prepared as a whitefoam (61%); NMR: 7.75 (s,1), 7.50-7.01 (m,10), 6.79 (d,1), 6.53 (dd,1),5.94 (d, 1), 5.41 (s,H), 3.03 (m,1), 2.65-2.45 (m,2), 2.33 (m,2), 2.16(s,3), 2.10-1.98 (m,6), 1.97 (s,3), 1.65 (broad m,2).

The compound of Example 15.f. is also a compound of the invention.

EXAMPLE 165-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazole

Using a procedure similar to that described in Example 10, except using5-[(1RS,2RS)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazole,the title compound was prepared as a white powder (77%); mp 128°-130°C.; NMR: 7.55 (s,1), 7.45-7.20 (broad m,12), 6.94 (d,1), 6.17 (s,1),5.47 (s,1), 5.03 (d,1), 3.00 (m,1), 2.82 (m,1), 2.66 (m,1), 2.47-2.16(broad m,8), 2.02 (s,3), 1.95 (m,1), 1.78-1.52 (broad m,2); MS:m/z=579((M+1), 37Cl), 577((M+1), 35Cl). Analysis for C₃₂ H₃₄ Cl₂ N₄ O₂·0.25 H2O; Calculated: C, 66.03; H, 5.97; N, 9.63; Found: C, 66.01; H,6.04; N, 9.37.

The starting material5-[(1RS,2RS)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazolewas prepared as follows.

a. 5-[2-(3,4-Dichlorophenyl)-4-pentenoyl]-1-phenylpyrazole. A solutionof oxalyl chloride (633 mg) in dichloromethane (5 mL) was cooled to -78°C. and was treated dropwise with dimethyl sulfoxide (442 mg) indichloromethane (2 mL). The resulting mixture was stirred at -78° C. for0.5 hours, was treated with a solution of5-[2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenylpyrazole (70:30anti/syn) (960 mg), prepared as described in Example 9.c., indichloromethane (5 mL). The mixture was stirred at -78° C. for 2 hours,was treated with triethylamine (1.30 g), warmed to room temperature andstirred for 1 hour. The mixture was poured into, water and extractedwith dichloromethane. The organic extract was washed (water, brine)dried, and evaporated to afford the ketone as a yellow oil (880 mg);NMR: 7.66 (d, 1), 7.46-7.36 (m,5), 7.25-7.22 (m,2), 7.11 (dd,1), 6.96(d, 1), 5.64 (m,1), 5.02 (m,2), 4.30 (t,1), 2.82 (m,1), 2.49 (m,1).

b.5-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenylpyrazole.Using a procedure similar to that described in Example 2, except using5-[(2RS)-2-(3,4-dichlorophenyl)-4-pentenoyl]-1-phenylpyrazole, the titlealcohol was obtained as a clear glass (87%); NMR: 7.55 (d,1), 7.46-7.36(m,5), 7.27 (d,1), 7.12 (d,1), 6.84 (dd,1), 6.21 (d,1), 5.31 (m,1), 4.81(m,3), 2.85 (m,1), 2.28 (m,1), 2.14 (m,1).

c.5-[(1RS,2RS)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenylpyrazole.Using a procedure similar to that described in Example 7.e., exceptusing5-[(1RS,2RS)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenylpyrazole,the acetate was obtained as a clear syrup (85%); NMR: 7.58 (d,1),7.50-7.38 (m,5), 7.23 (d,1), 7.02 (d,1), 6.74 (dd, 1), 6.20 (d, 1)),6.09 (d, 1), 5.33 (m,1), 4.84 (m,2), 2.90 (m,1), 2.29 (m,2), 1.99 (s,3).

d.5-[(1RS,2RS)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazole.Using a procedure similar to that described in Example 7.f., exceptusing5-[(1RS,2RS)-1-acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenylpyrazole,the aldehyde was prepared as an amber oil (97%); MS: m/z=419((M+1),37Cl), 417((M+1), 35Cl.

e.5-[(1RS,2RS)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazole.Using a procedure similar to that described in Example 7, except using4-acetamido-4-phenylpiperidine as the amine component and5-[(1RS,2RS)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazoleas the aldehyde component, the title compound was obtained as a whitefoam (65%; NMR: 7.58 (d,1), 7.48-7.21 (m,11), 7.09 (d, 1), 6.81 (dd, 1),6.22 (d, 1), 6.09 (d, 1), 5.39 (s,1), 3.06 (m,1), 2.51 (m,2), 2.31(m,2), 2.15-2.00 (m,7), 1.98 (s,3), 1.96 (s,3), 1.75 (m,1), 1.43 (m,1).

The compound of Example 16.e. is also a compound of the invention.

EXAMPLE 175-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenylpyrazole

Using a procedure similar to that described in Example 7, except using4-(2-oxoperhydropyrimidin-1-yl)piperidine as the amine component thetitle compound was prepared as a white powder; mp 174.5°-176° C.; NMR:7.55 (s,1), 7.44-7.22 (broad m,6), 7.15(s,1), 6.88 (d,1), 6.17 (s,1),5.06 (d,1), 4.57 (broad s,1), 4.40 (m,1), 3.28 (m,2), 3.20 (m,2), 3.08(broad d,1), 2.98-2.78 (broad m,2), 2.32-2.11 (broad m,4), 1.93 (m,3),1.78-1.52 (broad m,7); MS: m/z=544((M+1), 37Cl), 542((M+1), 35Cl).Analysis for C₂₈ H₃₂ Cl₂ N₅ O₂ ·0.25 H₂ O: Calculated: C, 61.59; H,6.00; N, 12.83; Found: C, 61.66; H, 6.10; N, 12.33.

The starting material 4-(2-oxoperhydropyrimidin-1-yl)piperidine wasprepared as follows.

a. 8-Benzyloxycarbonyl-1,4-dioxa-8-azaspiro[4.5]decane. Benzylchloroformate (57.0 g) was added dropwise to a solution of1,4-dioxa-8-azaspiro[4.5]decane (50.2 g) and pyridine (54.0 mL) indichloromethane (300 mL) at -5° C. The mixture was allowed to warm toambient temperature and was stirred overnight. The mixture was washed(1N hydrochloric acid, aqueous sodium bicarbonate), dried and evaporatedto give the benzyloxycarbonyl compound as an oil (92.9 g), which wasused in the next step without purification; NMR: 7.35 (m,5), 5.13 (s,2),3.96 (s,4), 3.59 (m,4), 1.67 (m,4); MS: m/z=278(M+1).

b. 1-Benzyloxycarbonyl-4-oxopiperidine. A solution of the abovebenzyloxycarbonyl compound (92.9 g) in trifluoroacetic acid (100 mL) andwater (20 mL) was heated at 50° C. for 1.5 hours, followed by a 2 minutereflux. The mixture was evaporated, neutralized with saturated aqueoussodium bicarbonate, diluted with water, and extracted withdichloromethane. The organic extracts were dried, evaporated, anddistilled (156°-164° C.; 11.33-12.00 Pa) to give the ketone as acolorless liquid (59 g); NMR: 7.37 (m,5), 5.18 (s,2), 3.80 (m,4), 2.46(m,4); MS: m/z=234(M+1).

c. 1-Benzyloxycarbonyl-4-(3-aminopropylamino)piperidine. The aboveketone (32.0 g) in methanol (250 mL) was added to a solution of1,3-diaminopropane (17.2 mL) and acetic acid (23.6 mL) in methanol (250mL). After 30 minutes, sodium cyanoborohydride (25.9 g) in methanol (250mL) was added in a single portion. After stirring overnight, the mixturewas evaporated and the resulting residue was dissolved in 1Nhydrochloric acid (100 mL). Concentrated hydrochloric acid was addeddropwise and stirring was continued until the evolution of gas ceased.The acidic aqueous mixture was extracted with dichloromethane(discarded), made basic to pH 10 with 10N sodium hydroxide, andextracted with dichloromethane. The latter dichloromethane extracts weredried and evaporated to give the diamine as a viscous, light yellow oil(25.4 g); NMR (CD₃ OD): 7.33 (m,5), 5.10 (s,2), 4.13 (m,2), 2.86 (m,2),2.65 (m,5), 1.90 (m,2), 1.65 (m,2), 1.23 (m,2); MS: m/z=292(M+1).

d. 1-Benzyloxycarbonyl-4-(2-oxotetrahydropyrimidin-1-yl)piperidine. Astirred solution of the above diamine (10.1 g) and1,1'-carbonyldiimidazole (6.2 g) in chloroform (250 mL) was heated atreflux for 2 hours. The mixture was washed with water, and the separatedorganic phase was dried, evaporated, and chromatographed, withdichloromethane:methanol (90:10) as the eluent, to give1-Benzyloxycarbonyl-4-(2-oxotetrahydropyrimidin-1-yl)-piperidine as awhite solid (7.4 g); NMR: 7.35 (m,5), 5.12 (s,2), 4.75 (m,1), 4.50(m,1), 4.26 (m,2), 3.27 (m,2), 3.13 (m,2), 1.89 (m,2), 1.63 (m,4); MS:m/z=318(M+1).

e. 4-(2-Oxoperhydropyrimidin-1-yl)piperidine. A solution of1-Benzyloxycarbonyl-4-(2-oxotetrahydropyrimidin-1-yl)piperidine (3.0 g)and 20% palladium hydroxide on carbon (0.410 g) in ethanol (100 mL) wasstirred for 3.5 hours under 1 atmosphere of hydrogen. The reactionmixture was filtered through diatomaceous earth and the filtrate wasevaporated to give the pyrimidone as a white solid (1.6 g); NMR (CD₃OD): 4.25 (m,1), 3.22 (m,4), 3.08 (m,2), 2.63 (m,2), 1.87 (m,2), 1.60(m,4); MS: m/z=184(M+1).

EXAMPLE 185-[(1S,2S)-4-(4-Acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-1-hydroxybutyl]-1-phenyltriazole

Using a procedure similar to that described in Example 10, exceptsubstituting5-[(1S,2S)-4-(4-acetamido-4-phenylpiperidino)-1-acetoxy-2-(3,4-dichlorophenyl)butyl]-1-phenyltriazole,for the acetoxy compound used therein, the title compound was preparedas a white powder; mp 124°-126° C.; NMR: 7.49-7.23 (broad m,12),7.19(s,1), 6.93 (d, 1), 5.57 (s,1), 5.10 (d,1), 3.03 (s,1), 2.92 (m,1),2.79 (m,1), 2.58-2.25 (broad m,5), 2.21 (m,2), 2.02 (broad s,4), 1.86(m,1), 1.47 (m,2); MS: m/z=580((M+1), 37Cl), 58), 578((M+1), 35Cl).Analysis for C₃₁ H₃₃ Cl₂ N₅ O₂ ·1.00 H₂ O: Calculated: C, 62.42; H,5.91; N, 11.74; Found: C, 62.39; H, 5.81; N, 11.59.

The starting material5-[(1S,2S)-4-(4-acetamido-4-phenyl-piperidino)-1-acetoxy-2-(3,4-dichlorophenyl)butyl]-1-phenyltriazole,which is also a compound of the invention, was prepared using a sequencesimilar to that described in Example 7 and the sub-parts thereof, exceptsubstituting 1-phenyl-1,2,3-(1H)-triazole for the 1-phenylpyrazole usedin 7.c. and substituting 4-acetamido-4-phenylpiperidine for the4-hydroxy-4-phenylpiperidine used in the reductive amination.

EXAMPLE 195-[(1S,2S)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyltriazole

Using a procedure similar to that described in Example 10, exceptsubstituting5-[(1S,2S)-4-(4-acetamido-4-phenylpiperidino)-1-acetoxy-2-(3,4-dichlorophenyl)butyl]-1-phenyltriazolefor the acetoxy compound used therein, the title compound was preparedas a white powder; mp 130°-132° C.; NMR: 7.52 (s,1), 7.47 (m,3), 7.26(m,2), 7.20 (d,1), 7.11 (s,1), 6.86 (d,1), 5.10 (d, 1), 4.57 (s,1), 4.48(m,1), 3.28 (m,2), 3.18 (m,2), 3.08 (broad d,1), 2.98 (m,1), 2.48-2.07(broad m,4), 2.02-1.51 (broad m,11); MS: m/z=545((M+1), 37Cl),543((M+1), 35Cl). Analysis for C₂₈ H₃₂ Cl₂ N₅ O₂ ·0.25 H₂ O: Calculated:C, 61.59; H, 6.00; N, 12.83; Found: C, 61.66; H, 6.10; N, 12.33.

The starting material5-[(1S,2S)-4-(4-acetamido-4-phenylpiperidino)-1-acetoxy-2-(3,4-dichlorophenyl)butyl]-1-phenyltriazole,which is also a compound of the invention, was prepared using a sequencesimilar to that described in Example 7 and the sub-parts thereof, exceptsubstituting 1-phenyl-1,2,3-(1H)-triazole for the 1-phenylpyrazole usedin 7.c. and substituting 4-(2-oxoperhydropyrimidin-1-yl)piperidine forthe 4-hydroxy-4-phenylpiperidine used in the reductive amination.

EXAMPLE 205-[(1R,2S)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole

Using a procedure similar to that described in Example 10, except using5-[(1R,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyltriazole,the title compound was prepared as a white powder (73%); mp 116°-118°C.; NMR: 7.75 (s,1), 7.47 (m,3), 7.25 (m,2), 7.11 (d,1), 6.77 (s,1),6.55 (d,1), 4.85 (d,1), 4.59 (s,1), 4.44 (broad s,1), 3.31-3.17 (broadm,4), 3.00 (broad d,1), 2.86 (broad t,1), 2.50-2.40 (broad m,3),2.12-1.53 (broad m,12); MS: m/z=545((M+1), 37Cl), 543((M+1), 35Cl).Analysis for C₂₇ H₃₂ Cl₂ N₆ O₂ ·0.75 H₂ O: Calculated: C, 58.22; H,6.06; N, 15.09; Found: C, 58.31; H, 5.89; N, 15.09.

The starting material5-[(1R,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyltriazolewas prepared as follows.

a. (S)-2-(3,4-Dichlorophenyl)-4-pentenol. Using a procedure similar tothat described in Example 9.a., except using(S)-2-(3,4-dichlorophenyl)-4-pentenoic acid and purifying by bulb-to-bulb distillation, the alcohol was prepared as a clear oil whichcrystallized on standing to afford a waxy solid (86%); mp 33°-34.5° C.;[α]_(D) =+10.1 (c=3.475, methanol); NMR: 7.38 (d,1), 7.31 (d, 1), 7.05(dd,1), 5.65 (m,1), 4.99 (m,2), 3.77 (m,2), 2.83 (m,1), 2.51-2.28 (m,2).Analysis for C₁₁ H₁₂ Cl₂ O: Calculated: C, 57.17; H, 5.23; Found: C,57.17; H, 5.26.

b. (S)-2-(3,4-Dichlorophenyl)-4-pentenal. Using a procedure similar tothat described in Example 9.b., except using(S)-2-(3,4-dichlorophenyl)-4-pentenol, the aldehyde was prepared as apale yellow syrup (99%), which was used immediately in the next step,and was found racemize on standing; MS: m/z=231((M+1), 37Cl), 229((M+1),35Cl).

c.5-[(1R,2S)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.Lanthanum (III) chloride (3.24 g) was dried (140° C., 0.2 torr) for 2.5hours, was cooled to room temperature under nitrogen and suspended intetrahydrofuran (25 mL). The suspension was stirred for 16 hours. In aseparate flask, a solution of n-butyllithium (2.27 mL of a 2.44Msolution in hexanes) and tetrahydrofuran (5 mL) was cooled to -50° C.and was treated dropwise with a solution of 1-phenyl-1,2,3-(1H)triazole(760 mg) in tetrahydrofuran (10 mL). The resulting solution was stirredat -50° C. for 1 hour, transferred via cannula onto the cold (-78° C.)lanthanum chloride/tetrahydrofuran suspension, stirred at -50° C. for 1hour, and was treated with a solution of(S)-2-(3,4-dichlorophenyl)-4-pentenal (1.00 g) in tetrahydrofuran (25mL). The mixture was stirred for 1 hour at -50° C.; warmed to 0° C. andquenched by addition of 1% aqueous acetic acid (50 mL). The mixture wasdiluted with 1% aqueous acetic acid and extracted with ethyl acetate.The organic extract was washed (brine, 1% aqueous acetic acid), dried,and evaporated to leave a yellow syrup. Purification by radialchromatography (2 mm SiO2, 80:20 hexane/ethyl acetate, 50:50hexane/ethyl acetate, 2 runs, one-half of crude material on each run)afforded the alcohol as a pale yellow foam (502 mg); NMR: 7.70 (s,1),7.57-7.48 (m,3), 7.23-7.16 (m,3), 6.86 (d,1), 6.62 (dd,1), 5.45 (m,1),4.92 (m,3), 2.90 (m,1), 2.74 (m,1), 2.38 (m,1).

Also isolated from the chromatographic purification was the (1S,2S)diastereomer as a pale yellow oil (420 mg); NMR: 7.56 (s,1), 7.56-7.16(m,7), 6.84 (dd,1), 5.38 (m,1), 5.08 (m,1), 4.85 (m,2), 2.88 (m,1),2.44-2.21 (m,2).

d.5-[(1R,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.Using a procedure similar to that described in Example 7.e., exceptusing5-[(1R,2S)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole,the acetoxy compound was prepared as a clear syrup (84%); NMR: 7.76(s,1), 7.49-7.45 (m,3), 7.19-7.08 (m,2), 6.75 (d,1), 6.49 (dd,1), 5.92(d,1), 5.36 (m,1), 4.91 (m,2), 3.00 (m,1), 2.74 (m,1), 2.32 (m,1).

e.5-[(1R,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole.Using a procedure similar to that described in Example 7.f., exceptusing5-[(1R,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole,the aldehyde was prepared as a white foam (98%); NMR: 9.63 (s,1), 7.81(s,1), 7.52-7.45 (m,5), 7.18-7.12 (m,3), 6.80 (d,1), 6.56 (dd,1), 5.89(d,1), 3.63 (m,1), 2.98-2.73 (m,2).

f.5-[(1R,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)triazole.Using a procedure similar to that described in Example 7, except using4-(2-oxoperhydropyrimidin-1-yl)piperidine and5-[(1R,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole,the title compound was prepared as a white foam (34%); MS:m/z=587((M+1), 37Cl), 585((M+1), 35Cl).

The compound of Example 20.f. is also a compound of the invention.

The title compound can alternatively be prepared as follows.

g. A solution of 0.709 g of the compound of Example 22, in 40 mL ofmethanol was treated with 2.7 mL of 0.9N lithium hydroxide. Afterstirring for 1 hour the reaction mixture was evaporated and theresulting product was purified by rotory chromatograph using 39:1chloroform:methanol to afford the desired product; mp: 115°-117° C.; MS:m/z=542(M+1); NMR (CD3OD): 2.0 (m,12), 3.0 (m,3), 3.5 (m,4), 4.17 (m,1),4.91 (m,1), 6.82 (dd,1, J=2, 8), 7.05 (d,1, J=2), 7.27 (m,3), 7.61(m,3), 7.88 (s,1); Analysis for C27H32N6O2Cl2: Calculated: C, 59.66; H,5.93; N, 15.46; Found: C, 58.75; H, 5.95; N, 14.78.

EXAMPLE 215-[(1R,2S)-4-(4-Acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-1-hydroxybutyl]-1-phenyl-1,2,3-(1H)-triazole

Using a procedure similar to that described in Example 10, exceptsubstituting5-[(1R,2S)-4-(4-acetamido-4-phenylpiperidino)-1-acetoxy-2-(3,4-Dichlorophenyl)butyl]-1-phenyl-1,2,3-(1H)-triazolefor the acetoxy compound used therein, the title compound was preparedas a white powder; mp 129.5°-131.5° C.; NMR: 7.73 (s,1), 7.48 (broadm,3), 7.35 (m,3), 7.26 (m,4), 7.12 (d,1), 6.80 (s,1), 6.56 (d,1), 5.54(s,1), 4.86 (d, 1), 3.01-2.75 (m,3), 2.59-2.18 (broad m,9), 2.03 (broads,4), 1.78 (m,1); MS: m/z=580 ((M+1), 37Cl), 578((M+1), 35Cl). Analysisfor C₃₁ H₃₃ Cl₂ N₅ O₂ ·0.25 H₂ O: Calculated: C, 63.86; H, 5.79; N,12.01; Found: C, 63.76; H, 5.77; N, 11.53.

The starting material5-[(1R,2S)-4-(4-Acetamido-4-phenylpiperidino)-1-acetoxy-2-(3,4-dichlorophenyl)butyl]-1-phenyl-1,2,3-(1H)-triazole,which is also a compound of the invention, was prepared using aprocedure similar to that described in Example 20.f., exceptsubstituting 4-acetamido-4-phenylpiperidine for the4-(2-oxoperhydropyrimidin-1-yl)piperidine used therein.

EXAMPLE 225-[(1R,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxo-perhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

A solution of 0.417 g of5-[(1S,2S)-1-Acetoxy-2-(3,4-dichloro-phenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazolein 20 mL of methanol was treated with 0.183 g of4-(2-oxoperhydropyrimidin-1-yl)piperidine and the pH of the reactionmixture was adjusted to 5.5 by adding glacial acetic acid. Afterstirring the reaction mixture for 15 minutes., 0.936 g of sodiumcyanoborohydride was added and the resulting mixture was stirred for 18hours. At the end of this period, the reaction mixture was diluted with3 mL of water and concentrated under reduced pressure. The residue wasdiluted with sodium chloride solution and extracted twice withchloroform. The combined organic layers were dried over anhydrous sodiumsulfate and concentrated under reduced pressure. The resulting oil waspurified by roto chromatography over silica gel to afford 0.27 g of thedesired material. This product was converted to the citrate salt bydissolving it in ether and treating with a citric acid solution inmethanol. The resulting solution was concentrated under reduced pressureand the resulting residue was triturated with ether. The oily materialthus obtained was dried under reduced pressure to afford 0.254 g of thedesired product; mp: 75°-77° C.; MS: m/z=585(M+1); NMR (CD3OD): 3.2(m,5), 3.62 (s,3), 4.3 (m,1), 5.9 (d,1, J=10), 6.74 (dd,1, J=2, 8), 7.04(m,1), 7.17 (m,2), 7.52 (m,3), 7.94 (s,1). Analysis for C₂₉ H₃₄ N₆ O₃Cl₂ ·1.15 C₆ H₈ O₇ ·0.05 H₂ O: Calculated C, 53.41; H, 5.41; N, 10.41;Found C, 53.77; H, 5.66; N, 9.75.

The intermediate5-[(1S,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared as follows.

a.5-[(1R,2S)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.A solution5-((S)-2-(3,4-dichlorophenyl)-4-pentenoyl)-1-phenyl-1,2,3-(1H)-triazole(3.11 g, prepared using a procedure similar to that described in Example7 sub-part c except substituting 1-phenyltriazole for the1-phenylpyrazole used therein) in 80 mL of anhydrous tetrahydrofuran wasadded to anhydrous lanthanum trichloride (prepared by heating 7.96 g oflanthanum trichloride heptahydrate under reduced pressure for 16h) andstirring the resulting suspension for 2.5 hours. At the end of thisperiod the reaction mixture was cooled to -78° C., treated with 0.402 gof sodium borohydride and stirred for 1 hour. Upon allowing to warm tothe room temperature, the reaction mixture was treated with additional0.4 g of sodium borohydride and stirred for 16 hours. At the end of thisperiod 50 mL of water and 20 mL of 1N sodium hydroxide were added andthe reaction mixture was extracted with chloroform. The organic layerwas washed with brine and the aqueous layers were extracted with twoportions of chloroform. The organic layers dried and evaporated toafford the crude material. This product was purified by chromatography,with 70:30 hexane:ethyl acetate as the eluent to give 0.52 g of the(1S,2S) isomer; mp 50°-51° C.; [a]_(D) =-89.47° (c=0.57, EtOH); MS:m/z=372(M+1); NMR (CDCl3): 2.22 (m,1), 2.35(m,1), 2.86(m,1), 4.85(m,2),4.99(d,1, J=6.6), 6.87 (dd,1, J=2, 8), 7.18 (d,1, J=2), 7.26 (m,1), 7.37(m,2), 7.5 (m,4). Isomer 4: mp 116°-117° C.; {a}D 52, C=0.61 ETOH; MS:m/z 372(M+1); and 0.52 g of the desired (1R,2S) isomer; NMR (CDCl3): 2.4(m,1), 2.6 (m,1), 2.7 (m,1), 4.93 (m,3), 5.46 (m,1), 6.65 (dd,1, J=2.1,8.4), 6.87 (d,1, J=2), 7.23 (m,3), 7.53 (m,3), 7.73 (s,1).

b.5-[(1R,2S)-1-Acetoxy-2-(3,4-Dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.A solution 1.14 g of the compound from (a) in 20 mL of dichloromethanewas treated with 0.344 mL of acetic anhydride, 0.47 mL of triethylamine,followed by 0.037 g of dimethylaminopyridine. Upon stirring for 16 hoursthe reaction mixture was diluted with dichloromethane and washed with 1Nhydrochloric acid. The aqueous layer was extracted with dichloromethaneand the combined organic layers were dried and evaporated to afford 1.28g of the acetate which had a mass spectrum and NMR similar to thematerial in sub-part f. below.

c.5-[(1S,2S)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole.A solution of 1.28 g of the compound from (b) in 10 mL of ethercontaining 5 mL of tetrahydrofuran and 10 mL of water was treated with0.3 mL of 0.16M osmium tetroxide solution followed by 1.449 g of sodiumperiodate in 3 portions. The reaction mixture was stirred for 3 hoursand diluted with water. Extraction with ethyl acetate, washing theorganic layer with water, drying the organic layer with anhydrous sodiumsulfate and evaporation afforded 1.1 g of the aldehyde; NMR (CDCl3):2.14 (s,3), 2.81 (m,2), 3.59(m 1), 5.90(d, J=10 Hz, 1), 6.57(d,d, J1=2Hz, J2=8 Hz, 1), 7.1 (m,3), 7.45 (m,3), 7.80 (s,1), 9.62 (t,J=1).

The (1R,2S) alcohol described at (a) can be prepared from the (1S,2S)alcohol which was also isolated in (a) using the sequence describedbelow.

d.5-[(1S,2S)-2-(3,4-Dichlorophenyl)-1-mesyloxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.A solution of 1.74 g of the (1S,2S) alcohol from (a) in 25 mL ofanhydrous pyridine at 0° C. was treated with 5.59 mL of methane sulfonylchloride. The resulting reaction mixture was stirred at 0° C. for 45minutes and was warmed to room temperature for 1.5 hours. The reactionmixture was poured in ice water and extracted with four portions ofdichloromethane. The organic layers were washed with water until theaqueous layers were neutral, dried over anhydrous sodium sulfate andevaporated to afford 2.3 g of the mesylate; NMR (CDCl3): 2.37 (m,2),2.79 (s,3), 2.93 (m,1), 4.96 (m,2), 5.35 (m,1), 5.93 (d,1, J=6), 6.75(dd,1, J=2, J=8), 7.04 (d,1, J=2), 7.40 (m,3), 7.58 (m,3), 7.83 (m,1).

e.5-[(1R,2S)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.A solution of 0.56 g of (d) in 16 mL of dimethylsulfoxide and 24 mL ofdimethylformamide was treated with 0.327 g of 18-crown-6(1,4,7,10,13,16-hexaoxacyclooctadecane). Upon cooling to 0° C. thereaction mixture was treated with 0.308 g of potassium super oxide andstirred for 10 minutes. The reaction mixture was diluted with water,treated with sodium thiosulfate and extracted with 4 portions of ether.The organic layers were washed with sodium chloride solution, dried overanhydrous sodium sulfate and evaporated to afford the crude product.This material was purified by chromatography, with 6:4 hexane:ethylacetate as the eluent to give the alcohol which had a mass spectrum andan NMR similar to the described for the (1R,2S) isomer in (a).

f.5-[(1R,2S)-1-Acetoxy-2-(3,4-Dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.A solution 0.652 g of (e) in 10 mL of dichloromethane was treated with0.196 mL of acetic anhydride, 0.289 mL of triethylamine followed by0.021 g of dimethylaminopyridine. Upon stirring for 1.5 hours thereaction mixture was diluted with dichloromethane and washed with 1Nhydrochloric acid. The aqueous layer was extracted with dichloromethaneand the combined organic layers were dried and evaporated to afford 0.68g of the acetoxy compound; MS: m/z=416(M+1); NMR (CDCl3): 2.03 (s,3),2.31 (m,1), 2.62 (m,1), 3.02 (td,1, J=10, 4), 4.9 (m 2), 5.4 (m,1), 5.9(d,1, J=10), 6.50 (dd,1, J1=2, 8), 6.76 (d, 1, J=2), 7.16 (d,1, J=8),7.18 (m,2), 7.48 (m,3), 7.76 (s,1).

EXAMPLE 235-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxo-perhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

Using a procedure similar to that described in Example 22 and thesub-parts thereof, except replacing the5-((S)-2-(3,4-dichlorophenyl)-4-pentenoyl)-1-phenyl-1,2,3-(1H)-triazoleused in sub-part (a), with the racemic5-(2-(3,4-dichlorophenyl)-4-pentenoyl)-1-phenyl-1,2,3-(1H)-triazole, thetitle compound was prepared; mp 135°-140° C.; MS and NMR similar to thatdescribed for the compound of Example 22.

EXAMPLE 245-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(2-oxo-perhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole

The compound of Example 23 was subjected to a procedure similar to thatdescribed in Example 20 sub-part (f) to give the title compound; mp110°-115° C.; MS and NMR were similar to that described for the compoundof Example 20.

EXAMPLE 255-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-[4-(2-oxopiperidino)piperidino]butyl]-1-phenyl-1,2,3-(1H)-triazole

Using a procedure similar to that described in Example 23, exceptreplacing the 4-(2-oxoperhydropyrimidin-1-yl)piperidine used thereinwith 4-(2-oxopiperidino)piperidine, stirring for 2 hours instead of 18hours, and eliminating the conversion to the citrate salt, the titlecompound was prepared; mp 65°-67° C.; MS: m/z=588(M+1); NMR (CD3OD): 1.7(m,12), 2.13 (s,3), 2.35 (m,2), 2.85 (m,2), 3.13 (m,3), 4.29 (m,1), 5.92(d,1, J=10), 6.7 (dd,1, J=2, 8), 6.98 (d,1, J=2), 7.22 (m,3), 7.50(m,3), 7.9 (s,1). Analysis for C₃₀ H₃₅ N₅ O₃ Cl₂ ·2.0 H₂ O: Calculated:C, 58.06; H, 6.33; N, 11.28; Found: C, 57.54; H, 5.61; N, 11.13.

The intermediate 4-(2-oxopiperidino)piperidine can be prepared asdescribed in International Patent Application Publication NumberW0/148,184 at Example 8 sub-parts a)-c).

EXAMPLE 265-[(1R,2S)-2-(3,4-Dichlorophenyl)-1-hydroxy-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole

Using a procedure similar to that described in Example 20 sub-part (g)except replacing the5-[(1R,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleused therein, with5-[(1R,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolethe title compound was prepared; mp 75-80; MS: m/z 546 (M+1);NMR(CD3OD): 1.57(m,2), 1.77(m,7), 2.09(m,3), 2.27(m, 4), 2.92(m,3),3.21(m,2), 4.34(m,1), 6.7(d,d,J1=2 Hz, J2=8 Hz, 1), 7.01(d, J=2 Hz, 1),7.22(m,3), 7.50(m,3), 7.9(s, 1). Analysis for C₂₈ H₃₃ N₅ O₂ Cl₂ ·1.0 H₂O: Calculated C, 59.50; H, 5.93; N, 12.21; Found C, 59.90; H, 6.29; N,12.49.

The intermediate5-[(1R,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared using a procedure similar to that described in Example 22except the 4-(2-oxo-perhydropyrimidin-1-yl)piperidine used in Example 22was replaced with 4-(2-oxopiperidino)piperidine, the reaction wasallowed to stir for for 2 hours instead of 18 hours, and the conversionto the citrate salt was not performed.

EXAMPLE 275-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-hydroxy-4-[4-(2-oxopiperidino)piperidino]butyl]-1-phenyl-1,2,3-(1H)-triazole

5-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-[4-(2-oxopiperidino)piperidino]butyl]-1-phenyl-1,2,3-(1H)-triazolewas subjected to a procedure similar to that described in Example 20sub-part (g) to give the title compound; mp 85°-90° C.; mass spectrumand NMR were similar to that described for the compound of Example 26.Analysis for C₂₈ H₃₃ N₅ O₂ Cl₂ ·1.0 H₂ O: Calculated C, 59.50; H, 5.93;N, 12.21; Found C, 59.67; H, 5.93; N, 12.31.

EXAMPLE 285-[(1R,2S)-2-(3,4-dichlorophenyl)-1-hydroxy-4-[4-(methylaminocarbonyl)-4-(2-oxopiperidino)piperidino]butyl]-1-phenyl-1,2,3-(1H)-triazole

5-[(1R,2S)-1-Acetoxy-2-(3,4-dichloro-phenyl)-4-[4-(methylaminocarbonyl)-4-(2-oxopiperidino)piperidino]-butyl]-1-phenyl-1,2,3-(1H)-triazolewas subjected to a procedure similar to that described in Example 20sub-part (g), except the product was converted to the citrate salt; mp95°-97° C.; MS: m/z=599(M+1); NMR (CD3OD): 1.7 (m,4), 2.3 (m,6), 2.35(m,2), 2.85 (m,16), 3.43 (m,2), 6.7 (dd,1, J=2, 8), 7.06 (d,1, J=2),7.16 (m,3), 7.57 (m,3), 7.9 (s,1). Analysis for C₃₀ H₃₆ N₆ O₃ Cl₂ ·0.8H₂ O: Calculated C, 52.9; H, 5.63; N, 9.95; Found C, 53.29; H, 5.74; N,9.07.

The intermediate5-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-[4-(methylaminocarbonyl)-4-(2-oxopiperidino)piperidino]butyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared using a procedure similar to that described in Example 22,except replacing the 4-(2-oxoperhydropyrimidin-1-yl)piperidine usedtherein, with 4-(methylaminocarbonyl)-4-(2-oxo-piperidino)piperidine,and allowing the reaction to stir for 11 days. The acetoxy compound isalso a compound or=f the invention.

The intermediate 4-(methylaminocarbonyl)-4-(2-oxopiperidino)piperidinewas prepared as follows.

a. 8-Benzyl-1,3,8-triazaspiro[4.5]decane-2,4-dione.1-Benzyl-4-piperidone (100 g) was added in a single portion to amechanically stirred suspension of ammonium carbonate (488.5 g) andsodium cyanide (70.0 g) in water (700 mL) and ethanol (700 mL). Thereaction mixture was stirred at 60° C. for 12 hours. The inorganic saltsdissolve gradually in the solution and spirohydantoin crystals formed.Upon cooling to room temperature, the solids were collected byfiltration, washed with warm water (2 L), recrystallized from 80%ethanol (2 L), washed with ethanol, and dried in a vacuum oven at 50° C.to give the hydantoin (122 g) as a white solid; MS: m/z=260(M+1); NMR(DMSO-d₆): 10.64 (bs,1), 8.45 (broad s,1), 7.29 (m,5), 3.48 (s,2), 2.69(m,2), 2.28 (m,2), 1.81 (m,2), 1.51 (m,2).

b. 4-Amino-1-benzyl-4-carboxypiperidine. A stirred solution of thehydantoin (40.0 g) and lithium hydroxide monohydrate (32.4 g) in water(500 mL) was heated at reflux for 40 hours. The mixture was cooled toroom temperature, filtered to remove the white precipitate, and thefiltrate evaporated. The pH of the concentrate was adjusted from 12 to 5with concentrated hydrochloric acid and the solution was evaporated todryness. The residue was suspended in methanol to provide a whiteprecipitate that was filtered, washed with methanol, and air-dried togive the amine (32.7 g) as a white solid; MS: m/z=235(M+1); NMR(DMSO-d₆): 7.40 (m,5), 3.89 (m,2), 2.92 (m,4), 2.12 (m,2), 1.84 (m,2).

c. 4-Amino-1-benzyl-4-ethoxycarbonylpiperidine. Thionyl chloride (43.0mL) was added dropwise to a suspension of the amino-acid (23.0 g) inethanol (400 mL) at 0° C. to give a clear solution. The reaction mixturewas warmed to room temperature, refluxed for 5 hours, and stirredovernight at room temperature. The mixture was evaporated and strippedtwice from toluene. The resulting oil was dissolved in water, adjustedto pH 3 with 1N sodium hydroxide, neutralized with saturated aqueoussodium bicarbonate, and extracted with dichloromethane. The organicextracts were dried and evaporated to give the ester (21.5 g) as an oil;MS: m/z=263(M+1); NMR: 7.28 (m,5), 4.17 (q,2, J=7.1), 3.52 (s,2), 2.50(m,4), 2.13 (m,2), 1.54 (m,4), 1.27 (t,3, J=7.1).

d. 1-Benzyl-4-(5-chlorovaleramido)-4-ethoxycarbonylpiperidine.5-Chlorovaleryl chloride (13.2 g) in dichloromethane (50 mL) was addeddropwise to a solution of the above amino-ester (20.3 g) and pyridine(13.1 mL) in dichloromethane (250 mL) at 0° C., resulting in theformation of a thick slurry within 20 minutes. After being warmed toroom temperature overnight, the slurry was diluted with aqueous sodiumbicarbonate to give a clear, biphasic solution, which was furtherextracted with dichloromethane. The organic extracts were dried andevaporated to a light brown semi-solid. The material was suspended inether and filtered to give the amide (16.8 g) as a white solid; MS:m/z=381(M+1); NMR (CD₃ OD): 7.28 (m,5), 4.11 (q,2, J=7.1), 3.55 (m,4),2.68 (m,2), 2.26 (m,4), 2.05 (m,4), 1.75 (m,4), 1.21 (t,3, J=7.1).

e. 1-Benzyl-4-ethoxycarbonyl-4-(2-oxopiperidino)piperidine. A solutionof the above amide (16.8 g) in tetrahydrofuran (50 mL) was cannulatedinto a suspension of sodium hydride (2.1 g) in tetrahydrofuran (150 mL).After being stirred overnight, the reaction mixture was quenched withwater, concentrated (to remove tetrahydrofuran), diluted with water, andextracted with dichloromethane. The combined organic extracts were driedand evaporated. The crude product was chromatographed, withdichloromethane:methanol (gradient 97:3, 95:5) as eluent, to give1-benzyl-4-ethoxycarbonyl-4-(2-oxopiperidino)piperidine (13.2 g) as asolid; MS: m/z=345(M+1); NMR (CD₃ OD): 7.30 (m,5), 4.11 (q,2, J=7.1),3.54 (s,2), 3.44 (m,2), 2.66 (m,2), 2.52 (m,2), 2.32 (m,2), 2.20 (m,2),2.01 (m,2), 1.85 (m,2), 1.74 (m,2), 1.20 (t,3, J=7.1).

f. 4-Ethoxycarbonyl-4-(2-oxopiperidino)piperidine. A solution of1-benzyl-4-ethoxycarbonyl-4-(2-oxopiperidino)piperidine (12.4 g) and 20%palladium hydroxide on carbon (2.0 g) in ethanol (150 mL) was stirredovernight under hydrogen (1 bar). The reaction mixture was filteredthrough diatomaceous earth, and the filtrate was evaporated to give4-ethoxycarbonyl-4-(2-oxopiperidino)piperidine (9.1 g) as a viscous oil;MS: m/z=255(M+1); NMR (CD₃ OD): 4.13 (q,2, J=7.1), 3.44 (m,2), 2.95(m,4), 2.32 (m,2), 2.19 (m,2), 1.88 (m,4), 1.74 (m,2), 1.23 (t,3,J=7.1).

g. 1-Benzyloxycarbonyl-4-(ethoxycarbonyl)-4-(2-oxopiperidino)piperidine.4-(Ethoxycarbonyl)-4-(2-oxopiperidino)piperidine (9.0 g) indichloromethane (25 mL) was added to a solution ofN-(benzyloxycarbonyloxy)succinimide (8.8 g) and triethylamine (5.4 mL)in dichloromethane (150 mL). After 1.5 hours, the reaction mixture waswashed successively with 1.0N hydrochloric acid and saturated aqueoussodium bicarbonate. The separated organic layer was dried and evaporatedto give the title compound (11.6 g) as a light yellow solid; MS:m/z=389(M+1); NMR (CDCl₃ /CF₃ COOH): 7.37 (m,5), 5.16 (s,2), 4.28 (q,2,J=7.1), 4.09 (m,2), 3.40 (m,2), 3.28 (m,2), 2.53 (m,2), 2.34 (m,2), 1.83(m,6), 1.30 (t,3, J=7.1).

h. 1-Benzyloxycarbonyl-4-carboxy-4-(2-oxopiperidino)piperidine. Asolution of1-benzyloxycarbonyl-4-ethoxycarbonyl-4-(2-oxopiperidino)piperidine (11.4g) in tetrahydrofuran (150 mL), 1.0N sodium hydroxide (50 mL), andmethanol (volume necessary to obtain clear solution) was heated atreflux for 10 hours. The reaction mixture was evaporated and theresulting aqueous solution was diluted with water and extracted withdichloromethane to recover unreacted starting material (3.7 g). Theaqueous phase was acidified to pH 3 with 1.0N hydrochloric acid andextracted with dichloromethane. The combined organic extracts werewashed with water, dried, and evaporated to furnish a light yellowsolid. The material was suspended in ether and filtered to give thetitle compound (6.3 g) as a white solid; MS: m/z=361(M+1); NMR (CDCl₃/CF₃ COOH): 7.37 (m,5), 5.17 (s,2), 4.11 (m,2), 3.45-3.32 (m,4), 2.55(m,2), 2.37 (m,2), 1.94-1.78 (m,6).

i.1-Benzyloxycarbonyl-4-(methylaminocarbonyl)-4-(2-oxopiperidino)piperidine.A solution of1-benzyloxycarbonyl-4-carboxy-4-(2-oxopiperidino)piperidine, methylaminehydrochloride, 4-(dimethylamino)pyridine, triethylamine, and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride indichloromethane was stirred overnight. The reaction mixture was dilutedwith dichloromethane and washed successively with 1.0N hydrochloricacid, saturated aqueous sodium bicarbonate, and water. The separatedorganic layer was dried and evaporated to give the amide as ahygroscopic, white solid; NMR: 7.35 (m,5), 6.72 (m,1), 5.12 (s,2), 3.56(m,4), 3.30 (m,2), 2.78 (d,3, J=4.8), 2.43 (m,2), 2.27 (m,2), 2.20(m,2), 1.76 (m,4).

j. 4-(Methylaminocarbonyl)-4-(2-oxopiperidino)piperidine.1-Benzyloxycarbonyl-4-(methylaminocarbonyl)-4-(2-oxopiperidino)piperidinewas hydrogenated over 20% palladium hydroxide on carbon in ethanolovernight. The mixture was filtered through diatomaceous earth, and thefiltrate was evaporated to give the piperidine; MS: m/z=240(M+1); NMR(CD₃ OD): 3.45 (m,2), 3.10 (m,2), 2.96 (m,2), 2.68 (m,3), 2.32 (m,2),2.22 (m,2), 1.90 (m,4), 1.75 (m,2).

EXAMPLE 295-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-methoxy-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole

Using a procedure similar to that described in Example 22, exceptreplacing the5-[(1S,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazoleused therein with5-[(1RS,2SR)-2-(3,4-dichloro-phenyl)-1-methoxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole,the title compound was prepared; mp 68-70; MS: m/z 535(M+1); NMR(CD₃OD): 1.28 (m,4), 2.0 (m,12), 2.3 (m,1), 2.85 (m,3), 3.2 (m,4), 3.36(s,3), 4.09 (m,1), 4.58 (d,1, J=9), 6.77 (dd, 1, J=2, 8), 7.00 (d,1,J=2), 7.21 (m,3), 7.55 (m,3), 7.89 (s,1). Analysis for C₂₈ H₃₄ N₆ O₂ Cl₂·0.7 H₂ O: Calculated C, 58.80; H, 6.27; N, 14.69; Found C, 58.86; H,6.53; N, 13.11.

The intermediate5-[(1S,2S)-2-(3,4-dichlorophenyl)-1-methoxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared as follows.

a.5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-methoxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.A solution of5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole(0.857 g) in 10 mL of tetrahydrofuran was added to a suspension of0.0549 g of sodium hydride in 10 mL of tetrahydrofuran at 0° C. Afterstirring for 0.5 hours the reaction mixture was treated with a solutionof 0.712 mL of methyl iodide in 3 mL of tetrahydrofuran and stirred for2.5 hours. At the end of this period, the reaction mixture was treatedwith sodium chloride solution and extracted twice with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate and evaporatedto afford the crude product which was purified by rotatorychromatography to afford 0.525 g of the desired product; MS: m/z 388(M+1); NMR (CDCl3): 2.29 (m,1), 2.78 (m,2), 3.32 (s, 3), 4.4 (d,1), 4.9(m,2), 5.43 (m,1), 6.57 (dd,1, J=2, 8), 6.87 (d, 1, J=2), 7.1 (m,2),7.49 (m,3), 7.75 (s,1).

b.5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-methoxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole.Using a procedure similar to that described in Example 22 sub-part (c),except replacing the5-[(1R,2S)-1-acetoxy-2-(3,4-Dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazoleused therein, with5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-methoxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole,the aldehyde was prepared; MS: m/z 326(M+1); NMR(CDCl3): 2.68 (m,1), 3.0(m,1), 3.0 (s,3), 3.43 (m,1), 4.4 (d,1, J=9), 6.61 (dd,1, J=2 8), 6.83(d,1, J=2), 7.06 (m,2), 7.53 (m,3), 7.78 (s,1).

EXAMPLES 30-35

Using a reductive coupling procedure similar to that described inExample 7, except replacing the5-[(1S,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenylpyrazoleand 4-hydroxy-4-phenylpiperdine used therein, with the requisitealdehyde and piperidine components, the following compounds wereprepared.

EXAMPLE 30

5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-pivaloyloxy-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolecitrate salt; NMR (selected signals): 7.68 (s,1), 7.44 (m,2), 7.27(m,2), 7.10 (d,1), 6.79 (m,1), 6.50 (d,1), 5.88 (d,1), 4.60 (m,1), 4.24(m,1). Analysis for C₃₂ H₄₀ Cl₂ N₆ O₃ ·1.1 C₆ H₈ O₇ ·0.5 H₂ O;Calculated: C, 54.68; H, 5.92; N, 9.91; Found C, 54.93; H, 6.07; N 9.68.

EXAMPLE 31

5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-pivolyloxy-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolecitrate salt; NMR (selected signals):7.68 (s,1), 7.47 (m,2), 7.27 (m,2),7.08 (d,1), 6.78 (d,1), 6.48 (dd,1), 5.85 (d,1), 4.45 (m,1); Analysisfor C₃₃ H₄₁ Cl₂ N₅ O₃ ·C₆ H₈ O₇·H₂ O; Calculated: C, 55.98; H, 6.14; N,8.37; Found C, 56.23; H, 6.00; N 8.26.

EXAMPLE 32

5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-benzoyloxy-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolecitrate salt; NMR (selected signals):8.07 (d,1), 7.77 (s,1), 7.63 (m,1),7.49 (m,3H), 7.15 (d,1), 6.61 (dd,1), 6.21 (d,1); Analysis for C₃₅ H₃₇Cl₂ N₅ O₃ ·1.2 C₆ H₈ O₇ ; Calculated: C, 56.35; H, 5.23; N, 9.57; FoundC, 56.25; H, 5.57; N 9.32.

EXAMPLE 33

5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-benzoyloxy-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolecitrate salt; NMR (selected signals):8.08 (d, 1), 7.54 (m,1), 7.49 (m,3H), 7.32 (m,1), 7.12 (d,1), 6.61 (dd,1), 6.21 (d,1), 4.45 (m,1);Analysis for C₃₅ H₃₇ Cl₂ N₅ O₃ ·C₆ H₈ O₇ ·H₂ O; Calculated: C, 57.48; H,5.53; N, 8.17; Found C, 57.215; H, 5.35; N 8.09.

EXAMPLE 34

5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-(4-methoxybenzoyloxy)-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolecitrate salt; NMR (selected signals): 8.03 (d, 1), 7.50 (m,2), 7.31(m,1), 7.14 (d,2), 6.99 (d,1), 6.85 (d,1), 6.60 (dd,1), 6.18 (d,1), 4.55(s,1), 4.23 (m,1), 3.90 (s,3); Analysis for C₃₅ H₃₈ Cl₂ N₆ O₄ ·1.1C₆ H₈O₇ ·0.5 H₂ O; Calculated: C, 55.35; H, 5.37; N, 9.16; Found C, 55.64; H,5.36; N 9.36.

EXAMPLE 35

5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-(4-methoxybenzoyloxy)-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazolecitrate salt; NMR (selected signals): 8.03 (d,1), 7.52 (m,2), 7.32(m,1), 7.14 (d,1), 6.99 (d,2), 6.96 (d,1), 6.60 (dd,1), 6.19 (d,1), 4.45(m,1), 3.90 (s,3); Analysis for C₃₆ H₃₉ Cl₂ N₅ O₄ ·1.1 C₆ H₈ O₇ ·0.5 H₂O; Calculated: C, 57.04; H, 5.48; N, 7.80; Found C, 56.89; H, 5.43; N7.88.

The intermediate aldehydes used in Examples 30-35 were prepared asfollows.

EXAMPLES 30a.-35a.

Using a procedure similar to that described in Example 7 sub-part (e),except replacing the acetic anhydride used therein, with the requsiteacid chloride, the following compounds of formula XXIII, wherein R⁹ hasthe indicated value were prepared.

EXAMPLE 30a. AND EXAMPLE 31a.

R⁹ =pivaloyl; MS (CI) 458 (M+H).

EXAMPLE 32a. AND EXAMPLE 33a.

R⁹ =benzoyl; MS (CI) 478 (M+H).

EXAMPLE 34a. AND EXAMPLE 35a.

R⁹ =4-methoxybenzoyl; MS (CI) 508 (M+H).

EXAMPLES 30b.-35b.

Using a procedure similar to that described in Example 7 sub-part (f),except replacing the5-[(1S,2S)-1-acetoxy-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenyl-pyrazoleused therein, with the requsite alkene, the following aldehydes offormula XXIV wherein R¹⁰ has the indicated value were prepared.

EXAMPLE 30b. AND EXAMPLE 31b.

R¹⁰ =pivaloyl; MS (CI): 460 (M+H).

EXAMPLE 32b. AND EXAMPLE 33b.

R¹⁰ =benzoyl; MS (CI): 480 (M+H).

EXAMPLE 34b. AND EXAMPLE 35b.

R¹⁰ =4-methoxybenzoyl; MS (CI): 510 (M+H).

EXAMPLE 365-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-acetylthio-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

To a stirred solution of5-[(1RS,2SR)-1-acetylthio-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole(0.43 g) in methanol (13 mL) was added4-(2-oxoperhydropyrimidin-1-yl)piperidine (0.218 g) and the pH adjustedto approximately 6.0 with a few drops of acetic acid. The solution waschilled (ice bath) and sodium cyanoborohydride (0.087 g) was added inone portion. After 10 minutes the ice bath was removed and the solutionwas stirred at room temperature overnight. Water was added and thereaction mixture made basic using 1N NaOH. The mixture was extractedwith ethyl acetate and the combined organic layer dried, filtered, andevaporated to yield a white solid (0.60 g). To the solid dissolved in asmall amount of methanol was added anhydrous citric acid (0.188 g). Themethanol was removed in vacuo, diethyl ether (10 mL) added and removedin vacuo. The process was repeated with a second portion of diethylether to yield the title compound (0.60 g) as a white solid; mp120°-125° C.; NMR: 1.47-3.39 (m,30) 4.09 (m,1) 4.77 (d,1) 6.23 (s,1),6.93-7.94 (m,9); MS (CI, CH₄): 601(M+1). Analysis for C₂₉ H₃₄ Cl₂ N₆ O₂S·1.0 C₆ H₈ O₄ ·1.0 H₂ O: Calculated: C, 51.79; H, 5.46; N, 10.35;Found: C, 51.97; H, 5.26; N, 9.97.

The intermediate5-[(1RS,2SR)-1-acetylthio-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared as follows.

a.5-[(1RS,2SR)-1-Acetylthio-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.A solution of freshly prepared cesium thioacetate (1.02 g) and5-[(1S,2S)-2-(3,4-dichlorophenyl)-1-mesyloxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole(2.0 g) in dimethylformamide (40 mL) were stirred at room temperatureovernight. The reaction mixture was partitioned between water and ethylacetate; the organic layer separated, washed with water (3×50 mL),dried, filtered, and evaporated. Chromatography, with hexane:ether asthe eluent 3:2 provided the thio-compound (1.20 g) as a clear tackysolid; NMR (CDCl₃): 2.17-2.28 (m,1) 2.38 (s,3) 2.57-2.65 (m,1) 2.88-2.96(m,1), 4.80-4.95 (m,3), 5.26-5.39 (m,1), 6.58 (dd,1), 7.00 (d,1), 7.18(d,1), 7.25 (m,2), 7.59 (m,3), 7.63 (s,1); MS (CI, CH₄): 432 (M+1).

b.5-[(1RS,2SR)-1-acetylthio-2-(3,4-dichlorophenyl)-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole.To a stirred solution of5-[(1RS,2SR)-1-acetylthio-2-(3,4-dichloro-phenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole(1.2 g) in diethyl ether (4 mL), water (4 mL), and tetrahydrofuran (2mL) was added a solution of 0.16M osmium tetroxide in water (0.26 mL).After 5 minutes sodium periodate (1.3 g) was added portionwise. After 2hours at room temperature water was added to the reaction mixture untilmost of the solids dissolved. The mixture was extracted with ethylacetate (2×50 mL); the combined organics dried, filtered, and thesolvent evaporated. Chromatography, with dichloromethane:ethyl acetate(9:1) as the eluent gave the title compound (1.0 g) as a tacky foam; NMR(CDCl₃): 2.39 (s,3) 2.71-2.97 (m 2), 3.54-3.62 (m,1), 4.93 (d,1), 6.67(dd,1), 6.89 (d,1), 7.17-7.21 (m,3), 7.52-7.57 (m,3), 7.70 (s,1), 9.52(s,1); MS (CI, CH₄): 434 (M+1).

EXAMPLE 375-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-acetylthio-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

To a stirred solution of5-[(1RS,2SR)-1-acetylthio-2-(3,4-dichlorophenyl)-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole(0.43 g) in methanol (13 mL) was added 4-(2-oxopiperidino)piperidine(0.218 g) and the pH adjusted to approximately 6.0 with a few drops ofacetic acid. The solution was chilled (ice bath) and sodiumcyanoborohydride (0.087 g) was added in one portion. After 10 minutesthe ice bath was removed and the solution stirred at room temperatureovernight. Water was added and the reaction mixture was made basic with1N NaOH. The mixture was extracted with ethyl acetate, the combinedorganics dried, filtered, and evaporated to yield a white solid (0.51g). To the solid dissolved in a small amount of methanol was addedanhydrous citric acid (0.163 g). The methanol was removed by evaporationand diethyl ether (10 mL) was added and removed by evaporation. Theprocess was repeated with a second portion of diethyl ether to yield thetitle compound (0.45 g) as a white solid; mp 120°-125° C.; NMR:1.48-3.33 (m,32), 4.24 (m,1), 4.77 (d,1), 6.93-7.94 (m,9); MS (CI, CH₄):600(M+1). Analysis for C₂₉ H₃₄ Cl₂ N₆ O₂ S·1.0 C₆ H₈ O₄ ·1.0 H₂ O:Calculated: C, 53.33; H, 5.59; N, 8.64; Found: C, 52.93; H, 5.36; N,8.87.

EXAMPLE 385-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-phenylcarbamoyloxy-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

To a solution5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-phenylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole(0.30 g) in methanol (10 mL) was added4-(2-oxoperhydropyrimidin-1-yl)piperidine (0.128 g) and the pH adjustedto approximately 6.0 with a few drops of acetic acid. The solution waschilled (ice bath) and sodium cyanoborohydride (0.057 g) was added inone portion. After 10 minutes the ice bath was removed and the solutionwas stirred at room temperature overnight. Water was added and thereaction mixture was made basic with 1N NaOH. The mixture was extractedwith ethyl acetate, the combined organics dried, filtered, andevaporated to yield a tan solid (0.40 g). To the solid dissolved in asmall amount of methanol was added anhydrous citric acid (0.116 g). Themethanol was evaporated and diethyl ether (10 mL) added and evaporated.The process was repeated with a second portion of diethyl ether to yieldthe title compound (0.31 g) as a tan solid; mp 130°-135° C.(d); NMR:1.47-3.41 (m,27), 4.10 (m,1), 5.86 (d,1), 6.21 (s,1), 6.85-7.98 (m,14);MS (CI, CH₄): 662(M+1). Analysis for C₃₄ H₃₆ Cl₂ N₇ O₃ ·1.0 C₆ H₈ O₄·1.0 H₂ O: Calculated: C, 55.11; H; 5.32; N; 11.24; Found: C, 54.88; H;5.27; N; 10.84.

The intermediate5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-phenylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared as follows.

a.5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-phenylcarbamoyloxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.To stirred solution of5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole(1.0 g) in dichloromethane (10 mL) was added phenyl isocyanate (0.32 g)and 2 drops of triethylamine and the mixture heated at reflux overnight.Chromatography, with dichloromethane as the eluent, gave the titlecompound (1.0 g) as a white solid; mp 180°-183° C.; NMR (CDCl₃)2.34-2.37 (m,1), 2.68 (m,1), 2.98-3.05 (m,1), 4.87-4.92 (m,2), 5.37-5.43(m,1), 6.01 (d,1), 6.49 (dd,1), 6.78 (d,1), 7.08-7.51 (m,11), 7.79(s,1); MS (Cl, CH₄): 493(M+1). Analysis for C₂₆ H₂₁ Cl₂ N₄ O₂ :Calculated: C, 63.42; H, 4.30; N, 11.38; Found: C, 63.44; H, 4.64, N,11.40.

b.5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-phenylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole

To a stirred solution of5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-phenylcarbamoyloxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole(1.0 g) in diethyl ether (4 mL), water (4 mL), and tetrahydrofuran (2mL) was added a solution of 0.16M osmium tetroxide in water (0.22 mL).After 5 minutes sodium periodate (0.96 g) was added portionwise. After 2hours at room temperature water was added to the reaction mixture untilmost of the solids dissolve. The mixture was extracted with ethylacetate (2×50 mL); the combined organic layers dried, filtered, and thesolvent evaporated to yield crude product as an oil. Chromatography,with dichloromethane:ethyl acetate (9:1) as the eluent gave the titlecompound 0.65 g (65%) as a white solid; NMR: 3.12 (d,2), 3.71-3.75(m,1), 5.84 (d,1) 6.8 (dd,1), 7.03 (t,1), 7.17-7.57 (m,11), 8.01 (s,1),9.54 (s,1); MS (CI, CH₄): 495(M+1).

EXAMPLE 395-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-phenylcarbamoyloxy-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

To a solution5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-phenylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole(0.35 g) in methanol (10 mL) was added 4-(2-oxopiperidino)piperidine(0.148 g) and the pH adjusted to approximately 6.0 with a few drops ofacetic acid. The solution was chilled (ice bath) and sodiumcyanoborohydride (0.062 g) was added in one portion. After 10 minutesthe ice bath was removed and the solution stirred at room temperatureovernight. Water was added and the reaction mixture made basic with 1NNaOH. The mixture was extracted with ethyl acetate, the combinedorganics dried, filtered, and evaporated to yield a tan solid (0.47 g).To the solid dissolved in a small amount of methanol was added anhydrouscitric acid (0.136 g). The methanol was evaporated and diethyl ether (10mL) added and evaporated. The process was repeated with a second portionof diethyl ether to yield the title compound (0.30 g) as a tan solid; mp145°-150° C. (d); NMR: 1.55-3.33 (m,32), 4.35 (m,1), 5.85 (d,1),6.76-7.99 (m,14); MS (CI, CH₄): 661(M+1). Analysis for C₃₅ H₃₈ Cl₂ N₆ O₃·1.2 C₆ H₈ O₄ ·2.0 H₂ O: Calculated: C, 54.61; H, 5.60; N, 9.05; Found:C, 54.34; H, 5.24; N, 9.07.

EXAMPLE 405-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-methylcarbamoyloxy-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

To a solution5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-methylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole(0.32 g) in methanol (10 mL) was added4-(2-oxoperhydropyrimidin-1-yl)piperidine (0.15 g) and the pH adjustedto approximately 6.0 with a few drops of acetic acid. The solution waschilled (ice bath) and sodium cyanoborohydride (0.065 g) was added inone portion. After 10 minutes the ice bath was removed and the solutionwas stirred at room temperature overnight. Water was added and thereaction mixture made basic with 1N NaOH. The mixture was extracted withethyl acetate, the combined organics dried, filtered, and evaporated toyield a white solid (0.35 g). To the solid dissolved in a small amountof methanol was added anhydrous citric acid (0.138 g). The methanol wasevaporated and diethyl ether (10 mL) added and evaporated. The processwas repeated with a second portion of diethyl ether to yield the titlecompound (0.39 g) as a white solid, mp 135°-140° C. (d); NMR: 1.49-3.41(m,30), 4.10 (m,1), 5.70 (d, 1), 6.22 (s,1), 6.78-7.87 (m,9MS (CI, CH₄):600(M+1). Analysis for C₂₉ H₃₄ Cl₂ N₇ O₃ ·1.1 C₆ H₈ O₄ ·1.0 H₂ O:Calculated: C, 51.59; H, 5.45; N, 11.83; Found: C, 51.35; H, 5.31; N,11.37.

The intermediate5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-methylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazolewas prepared as follows.

a.5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-methylcarbamoyloxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole.To a stirred solution of5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-hydroxy-4-pentenyl]-1-phenyl-1,2,3-(1H)-triazole(1.0 g) in dichloromethane (10 mL) was added methyl isocyanate (0.17 g)and 2 drops of triethylamine and the mixture stirred at refluxovernight. Evaporation provided the title compound 1.0 g (87%) as ayellow oil; NMR (CDCl₃): 2.22-2.35(m,1), 2.61-2.69(m,1), 2.85(d,3),2.86-2.98 (m,1), 4.84-4.90 (m,2), 5.30-5.44 (m 1), 5.89 (d,1), 6.46(dd,1), 6.74 (d,1), 7.06 (d,1), 7.22-7.26 (m,2), 7.43-7.51 (m,3), 7.73(s,1); MS (CI, CH₄): 431(M+1).

b.5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-methylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole.To a stirred solution of (a) (1.0 g) in diethyl ether (4 mL), water (4mL), and tetrahydrofuran (2 mL) was added a solution of 0.16M osmiumtetroxide in water (0.22 mL). After 5 minutes sodium periodate (1.1 g)was added portionwise. After 2 hours at room temperature water is addedto the reaction mixture until most of the solids dissolved. The mixturewas extracted with ethyl acetate (2×50 mL), the combined organic layerdried, filtered, and evaporated. Chromatography, withdichloromethane:ethyl acetate (8:2) as the eluent, provided the titlecompound 0.65 g as a clear oil; NMR: 2.56 (d,3), 2.93-3.02 (m,2),3.61-3.69 (m,1) 5.71 (d,1), 6.80 (d, 1), 7.15-7.56 (m,7), 7.90 (s,1),9.51 (s,1); MS (CI, CH₄): 433(M+1).

EXAMPLE 415-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-methylcarbamoyloxy-4-(2-oxopiperidino)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazoleCitrate Salt

To a stirred solution of5-[(1RS,2SR)-2-(3,4-dichlorophenyl)-1-methylcarbamoyloxy-4-oxobutyl]-1-phenyl-1,2,3-(1H)-triazole(0.30 g) in methanol (10 mL) was added 4-(2-oxopiperidino)]piperidine(0.145 g) and the pH adjusted to approximately 6.0 with a few drops ofacetic acid. The solution was chilled (ice bath) and sodiumcyanoborohydride (0.061 g) was added in one portion. After 10 minutesthe ice bath was removed and the solution was stirred at roomtemperature overnight. Water was added and the reaction mixture was madebasic with 1N NaOH. The mixture was extracted with ethyl acetate, thecombined organics dried, filtered, and evaporated to yield a white solid(0.42 g). To the solid dissolved in a small amount of methanol was addedanhydrous citric acid (0.135 g). The methanol was evaporated and diethylether (10 mL) added and evaporated. The process was repeated with asecond portion of diethyl ether to yield the title compound (0.40 g) asa white solid; mp >135° C. (d); NMR: 1.48-3.41 (m,32), 4.26 (m,1), 5.70(d, 1), 6.76-7.86 (m,9); MS (CI, CH₄): 599 (M+1). Analysis for C₃₀ H₃₅Cl₂ N₆ O₃ ·1.1 C₆ H₈ O₄ ·1.0 H₂ O: Calculated: C, 53.03; H, 5.69; N,10.14; Found: C, 52.86; H, 5.62; N, 10.08.

EXAMPLES 42-47

Using procedures similar to those described above, the followingcompounds were prepared.

EXAMPLE 42

2-[(1RS,2SR)-1-Acetoxy-2-(3,4-Dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyl]-1-phenylimidazole;mp 166°-168° C.; MS: m/z=578(M+1).

EXAMPLE 43

5-[(1RS,2SR)-1-Acetoxy-2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidino)butyl]-1-phenylpyrazole;mp 93°-95° C.; MS: m/z=578(M+1).

EXAMPLE 44

5-[2-(3,4-Dichlorophenyl)-1-hydroxy-2-methyl-4-[4-(2-oxoperhydropyrimidin-1-yl)piperidino]butyl]-1-phenylpyrazole;mp 125°-127.5° C.; MS: m/z=556(M+1).

EXAMPLE 45

5-[2-(3,4-Dichlorophenyl)-1-hydroxy-2-methyl-4-[4-(1-ethyl-1-hydroxypropyl)piperidino]butyl]-1-phenylpyrazole;mp 109.5°-111.5° C.; MS: 544(M+1).

EXAMPLE 46

5-[(1RS,2RS)-2-(3,4-Dichlorophenyl)-1-hydroxy-2-methyl-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazole;mp 133°-135° C.; MS: m/z=591(M+1).

EXAMPLE 47

5-[(1RS,2SR)-2-(3,4-Dichlorophenyl)-1-hydroxy-2-methyl-4-(4-acetamido-4-phenylpiperidino)butyl]-1-phenylpyrazole;mp 134.5°-136.5° C.; MS: m/z=591(M+1).

EXAMPLE 48

The following illustrates representative pharmaceutical dosages formswhich may be used for the therapeutic or prophylactic administration ofa compound of formula I or the N-oxide of the piperidino nitrogenindicated by Δ, or a pharmaceutically acceptable salt thereof, or aquaternary ammonium salt thereof (hereinafter referred to as `CompoundX`):

    ______________________________________                                        (i)    Tablet 1            mg/tablet                                          ______________________________________                                               `Compound X`        100.0                                                     Lactose             77.5                                                      Povidone            15.0                                                      Croscarmellose sodium                                                                             12.0                                                      Microcrystalline cellulose                                                                        92.5                                                      Magnesium stearate  3.0                                                                           300.0                                              ______________________________________                                        (ii)   Tablet 2            mg/tablet                                          ______________________________________                                               `Compound X`        20.0                                                      Microcrystalline cellulose                                                                        410.0                                                     Starch              50.0                                                      Sodium starch glycolate                                                                           15.0                                                      Magnesium stearate  5.0                                                                           500.0                                              ______________________________________                                        (iii)  Capsule             mg/capsule                                         ______________________________________                                               `Compound X`        10.0                                                      Colloidal silicon dioxide                                                                         1.5                                                       Lactose             465.5                                                     Pregelatinized starch                                                                             120.0                                                     Magnesium stearate  3.0                                                                           600.0                                              ______________________________________                                        (iv)   Injection 1 (1 mg/ML)                                                                             mg/mL                                              ______________________________________                                               `Compound X` (free acid form)                                                                     1.0                                                       Dibasic sodium phosphate                                                                          12.0                                                      Monobasic sodium phosphate                                                                        0.7                                                       Sodium chloride     4.5                                                       1.0 N Sodium hydroxide solution                                                                   q.s.                                                      (pH adjustment to 7.0-7.5)                                                    Water for injection q.s. ad 1 mL                                       ______________________________________                                        (v)    Injection 2 (10 mg/mL)                                                                            mg/mL                                              ______________________________________                                               `Compound X` (free acid form)                                                                     10.0                                                      Monobasic sodium phosphate                                                                        0.3                                                       Dibasic sodium phosphate                                                                          1.1                                                       Polyethylene glycol 400                                                                           200.0                                                     0.1 N Sodium hydroxide solution                                                                   q.s.                                                      (pH adjustment to 7.0-7.5)                                                    Water for injection q.s. ad 1 mL                                       ______________________________________                                        (vi)   Aerosol             mg/can                                             ______________________________________                                               `Compound X`        20.0                                                      Oleic acid          10.0                                                      Trichloromonofluoromethane                                                                        5,000.0                                                   Dichlorodifluoromethane                                                                           10,000.0                                                  Dichlorotetrafluoroethane                                                                         5,000.0                                            ______________________________________                                    

It will be appreciated that the above pharmaceutical compositions may bevaried according to well-known pharmaceutical techniques to accomodatediffering amounts and types of active ingredient `Compound X`. Theaerosol (vi) may be used in conjunction with a standard, metered doseaerosol dispenser. ##STR2##

What is claimed is:
 1. A compound of formula I:wherein Q¹ is a radicalof formula Ih:wherein L^(h) denotes a hydrocarbon radical in which the1-position is attached to M^(h) and the values of G^(h), J^(h), M^(h)and L^(h) are selected from: (a) G^(h) is a single bond; J^(h) is oxo orthioxo; M^(h) is oxy, thio or NR^(ha) ; and L^(h) is L^(ha) ; (b) G^(h)is a single bond; J^(h) is NR^(hb) ; M^(h) is NR^(ha) ; and L^(h) isL^(ha) ; (c) G^(h) is a double bond, J^(h) is OR^(ha), SR^(ha) orNR^(hc) R^(hd) ; M^(h) is nitrogen; and L^(h) is L^(ha) ; (d) G^(h) ismethylene which may bear one or two methyl substituents; J^(h) is oxo,thio or NR^(he) ; M^(h) is oxy, thio, sulfinyl, sulfonyl or NR^(ha) ;and L^(h) is L^(hb) ; (e) G^(h) is a single bond; J^(h) is oxo, thioxoor NR^(he) ; M^(h) is nitrogen; and L^(h) is L^(hc) ; (f) G^(h) ismethine, which may bear a (1-3C)alkyl substituent; J^(h) is oxo, thioxoor NR^(he) ; M^(h) is nitrogen; and L^(h) is L^(hd) ; (g) G^(h) iscis-vinylene, which may bear one or two methyl substituents; J^(h) isoxo, thioxo, or NR^(he) ; M^(h) is nitrogen; and L^(h) is L^(he) ; and(h) G^(h) is a single bond; J^(h) is oxo or thioxo: M^(h) is a singlebond: and L^(h) is L^(hf) ;wherein R^(ha) is hydrogen or (1-3C)alkyl;R^(hb) is hydrogen, (1-3C)alkyl, cyano, (1-3C)alkylsulfonyl or nitro;R^(hc) and R^(hd) are independently hydrogen or (1-3C)alkyl or theradical NR^(hc) R^(hd) is pyrrolidino, piperidino, morpholino,thiomorpholino (or its S-oxide) or piperazinyl (which piperazinyl maybear a (1-3C)alkyl substituent at the 4-position); R^(he) is hydrogen or(1-3C)alkyl; L^(ha) is ethylene, cis-vinylene, trimethylene ortetramethylene which radical L^(ha) itself may bear one or two methylsubstituents; L^(hb) is ethylene or trimethylene which radical L^(hb)itself may bear one or two methyl substituents; L^(hc) isprop-2-en-1-yliden-3-yl, which radical L^(hc) itself may bear one or twomethyl substituents; L^(hd) is cis-vinylene, which radical L^(hd) itselfmay bear one or two methyl substituents; L^(he) is methine, whichradical L^(he) itself may bear a (1-3C)alkyl substituent; and L^(hf) is4-oxabutan-1,4-diyl; Q² is a mono valent radical selected from hydroxy,(1-3C)alkoxy, --SR⁵, --OC(═O)R⁶, and --OC(═O)NR⁷ R⁸ ; or divalentradical selected from thioxo and oxo; R⁵ is hydrogen, (1-3C)alkanoyl,(1-3C)alkyl, phenyl, or phenyl(1-3C)alkyl, wherein any phenyl mayoptionally be substituted by 1-3 substituents selected from halo,(1-3C)alkyl, and (1-3C)alkoxy; R⁶ is (1-4C)alkyl, phenyl, orphenyl(1-3C)alkyl, wherein any phenyl may optionally be substituted by1-3 substituents selected from halo, (1-3C)alkyl, and (1-3C)alkoxy; R⁷and R⁸ are independently hydrogen, (1-4C)alkyl, phenyl, orphenyl(1-3C)alkyl, wherein any phenyl may optionally be substituted by1-3 substituents selected from halo, (1-3C)alkyl, and (1-3C)alkoxy; Q³is hydrogen or (1-3C)alkyl: Q⁴ is phenyl which may bear one or twosubstituents independently selected from halo, trifluoromethyl, hydroxy,(1-3C)alkoxy, (1-3C)alkyl and methylenedioxy; or Q⁴ is thienyl,imidazolyl, benzo[b]thiophenyl or naphthyl any of which may bear a halosubstituent; or Q⁴ is biphenylyl; or Q⁴ is carbon-linked indolyl whichmay bear a benzyl substituent at the 1-position; T is a carbon-linkedfive-membered aromatic ring containing 2-3 nitrogens, which issubstiteted at a ring position adjacent to the carbon-link by a group Q⁵; and Q⁵ is (1-6C)alkyl (which may contain a double or triple bond),(3-6C)cycloalkyl (which may contain a double bond), (3-6C)oxacycloalkyl(which may contain a double bond), aryl, aryl(1-3C)alkyl, or 5- or6-membered heteroaryl (or N-oxide thereof) consisting of carbon and oneto four heteroatoms selected from oxygen, sulfur and nitrogen, in whichan aryl or heteroaryl radical or portion of a radical may bear one ormore substituents on carbon selected from (1-3C)alkyl, (1-3C)alkoxy,methylenedioxy, halogeno, hydroxy, (1-4C)acyloxy and NR^(A) R^(B) inwhich R^(A) and R^(B) are independently hydrogen or (1-3C)alkyl, orR^(A) is hydrogen or (1-3C)alkyl and R^(B) is (1-4C)acyl; or the N-oxideof a piperidino nitrogen indicated by Δ; or a pharmaceuticallyacceptable salt thereof; or a quaternary ammonium salt thereof in whichthe piperidino nitrogen indicated by Δ is a quadricovalent ammoniumnitrogen wherein the fourth radical on the nitrogen R¹ is (1-4C)alkyl orbenzyl and the associated counterion A is a pharmaceutically acceptableanion.
 2. A compound of formula I as claimed in claim 1, wherein: Q² isa mono valent or divalent radical selected from hydroxy, acetoxy,(1-3C)alkoxy and oxo;or the N-oxide of a piperidino nitrogen indicatedby Δ; or a pharmaceutically acceptable salt thereof; or a quaternaryammonium salt thereof in which the piperidino nitrogen indicated by Δ isa quadricovalent ammonium nitrogen wherein the fourth radical on thenitrogen R¹ is (1-4C)alkyl or benzyl and the associated counterion A isa pharmaceutically acceptable anion.
 3. A compound of formula I asclaimed in claim 1 which is a compound of formula III: ##STR3## whereinQ^(1a) is a radical of formula Ih; andQ², T and Q⁵ have any of themeanings given in claim 1; or the N-oxide of a piperidino nitrogenindicated by Δ; or a pharmaceutically acceptable salt thereof; or aquaternary ammonium salt thereof in which the piperidino nitrogenindicated by Δ is a quadricovalent ammonium nitrogen wherein the fourthradical on the nitrogen R¹ is (1-4C)alkyl or benzyl and the associatedcounterion A is a pharmaceutically acceptable anion.
 4. A compound offormula I as claimed in claim 1, wherein aryl is phenyl; heteroaryl isfuryl, pyridyl or pyrimidinyl; halo is chloro or bromo; (1-3C)alkyl ismethyl, ethyl, propyl or isopropyl; (1-4C)alkyl is methyl, ethyl,propyl, isopropyl, butyl, isobutyl or t-butyl; (1-5C)alkyl is methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl;(1-6C)alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, pentyl, isopentyl, hexyl or isohexyl; (1-8C)alkyl is methyl,ethyl, propyl, isopropyl, isopentyl, 1-ethylpropyl, hexyl, isohexyl,1-propylbutyl, or octyl; (3-6C)cylcoalkyl is cyclopropyl, cyclopentyl orcyclohexyl; (3-7C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl orcycloheptyl; (3-8C)cycloalkyl is cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl; (3-6C)alkenyl is allyl, 2-butenyl or3-methyl-2-butenyl; (1-4C)alkanoyl is formyl, acetyl, propionyl, butyrylor isobutyryl; and (1-5C)alkanoyl is formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl or pivaloyl;or the N-oxide of apiperidino nitrogen indicated by Δ; or a pharmaceutically acceptablesalt thereof; or a quaternary ammonium salt thereof in which thepiperidino nitrogen indicated by Δ is a quadricovalent ammonium nitrogenwherein the fourth radical on the nitrogen R¹ is (1-4C)alkyl or benzyland the associated counterion A is a pharmaceutically acceptable anion.5. A compound of formula I as claimed in claim 1, whereinQ¹ is4-(2-oxoperhydropyrimidin-1-yl)piperidino; Q² is hydroxy; Q³ ishydrogen; Q⁴ is 3,4-dichlorophenyl or 3,4-methylenedioxyphenyl; T isimidazol-2-yl, pyrazol-4-yl, pyrazol-3-yl, pyrazol-5-yl, triazol-4-yl,or triazol-5-yl; and Q⁵ is phenyl; or the N-oxide of a piperidinonitrogen indicated by Δ; or a pharmaceutically acceptable salt thereof;or a quaternary ammonium salt thereof in which the piperidino nitrogenindicated by Δ is a quadricovalent ammonium nitrogen wherein the fourthradical on the nitrogen R¹ is methyl or benzyl; and the associatedcounterion A is chloride, bromide or methanesulfonate.
 6. A compound offormula I as claimed in claim 1, wherein Q¹ is4-(2-oxoperhydropyrimidin-1-yl)piperidino; and T is triazol-5-yl,or theN-oxide of a piperidino nitrogen indicated by Δ; or a pharmaceuticallyacceptable salt thereof; or a quaternary ammonium salt thereof in whichthe piperidino nitrogen indicated by Δ is a quadricovalent ammoniumnitrogen wherein the fourth radical on the nitrogen R¹ is (1-4C)alkyl orbenzyl and the associated counterion A is a pharmaceutically acceptableanion.
 7. A compound of formula I as claimed in claim 1 wherein J^(h) isoxo; Q² is hydroxy; Q³ is hydrogen; Q⁴ is phenyl which may bear one ortwo substituents selected from halo, trifluoromethyl and methylenedioxy;and Q⁵ is phenyl;or the N-oxide of a piperidino nitrogen indicated by Δ;or a pharmaceutically acceptable salt thereof; or a quaternary ammoniumsalt thereof in which the piperidino nitrogen indicated by Δ is aquadricovalent ammonium nitrogen wherein the fourth radical on thenitrogen R¹ is (1-4C)alkyl or benzyl and the associated counterion A isa pharmaceutically acceptable anion.
 8. A compound as described in claim1 which is5-[(1RS,2SR)-1-acetoxy-2-(3,4-dichlorophenyl)-4-(2-oxoperhydropyrimidin-1-yl)piperidino)butyl]-1-phenyl-1,2,3-(1H)-triazole; or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical composition comprising a compound of formula I;or theN-oxide of a piperidino nitrogen indicated by Δ; or a pharmaceuticallyacceptable salt thereof; or a quaternary ammonium salt thereof in whichthe piperidino nitrogen indicated by Δis a quadricovalent ammoniumnitrogen wherein the fourth radical on the nitrogen R¹ is (1-4C)alkyl orbenzyl and the associated counterion A is a pharmaceutically acceptableanion; as defined in claim 1; and a pharmaceutically acceptable diluentor carrier.
 10. A method of treating a disease in a human or othermammal in need thereof, in which NKA is implicated and antagonism of itsaction is desired, comprising: administering an effective amount of acompound of formula I;or the N-oxide of a piperidino nitrogen indicatedby Δ; or a pharmaceutically acceptable salt thereof; or a quaternaryammonium salt thereof in which the piperidino nitrogen indicated by Δ isa quadricovalent ammonium nitrogen wherein the fourth radical on thenitrogen R¹ is (1-4C)alkyl or benzyl and the associated counterion A isa pharmaceutically acceptable anion; as defined in claim
 1. 11. A methodtreating a disease as described in claim 10, wherein the disease isasthma.